https://proteopedia.org/api.php?action=feedcontributions&feedformat=atom&user=Elizabeth+M.+RatzProteopedia - User contributions [en]2026-09-30T03:35:12ZUser contributionsMediaWiki 1.43.8https://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3195260Sandbox Reserved 16072020-04-21T04:03:55Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
==Introduction==<br />
[https://en.wikipedia.org/wiki/Calcium_signaling Calcium] is a key signaling molecule involved in many physiological functions including muscle contraction, neuron excitability, cell migration and growth. <ref name="Giorgi C" /> The [https://en.wikipedia.org/wiki/Mitochondrion mitochondria] are important regulators of calcium in the body; they orchestrate the regulation of ATP production, cell death, and intracellular calcium signaling. <ref name="Fan C" /> The process of calcium regulation in the mitochondria is as follows: Calcium moves in one direction through the mitochondria from the [https://en.wikipedia.org/wiki/Intermembrane_space intermembrane space] through the [https://en.wikipedia.org/wiki/Inner_mitochondrial_membrane inner mitochondrial membrane] into the [https://en.wikipedia.org/wiki/Mitochondrial_matrix matrix]. The matrix is more negatively charged driven by the [https://en.wikipedia.org/wiki/Electron_transport_chain electron transport chain] which facilitates calcium movement with its concentration gradient. Maintaining this concentration gradient and the [https://en.wikipedia.org/wiki/Homeostasis homeostasis] of calcium in the mitochondria is the calcium uniporter (MCU). The MCU is a complex composed of regulatory subunits including mitochondrial calcium uptake (MICU), essential MICU regulator (EMRE), MCU regulatory subunit b (MCUb), and MCU regulator 1 (MCUR1). <ref name="Fan C" /> On the outside of the uniporter portion of the MCU are mitochondrial calcium uptake 1 and 2 (MICU1 and MICU2). MICU1 and MICU2 act as gatekeepers by setting the calcium uptake threshold for activation of MCU, only allowing calcium uptake at high calcium concentrations. MICU1 and MICU2 bind together and associate with another external subunit, EMRE, to regulate calcium acquisition by the MCU. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein. <ref name="Fan C" /><br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. This analysis led to the discovery of key residues within the structure of the MCU as well as providing a structural framework for understanding the mechanism by with the MCU functions. <ref name="Giorgi C" /><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a <scene name='83/837230/Ntermsymmetry/1'>dimer of dimers</scene>, described as <scene name='83/837230/Pyramid/2'>tetrameric truncated pyramid</scene>. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> The Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU (Figure 1). The transmembrane domain opens to the surface of the inner mitochondrial membrane, while the soluble domain, the coiled coil and the N-terminal domain reside inside the inner mitochondrial membrane, opening to the mitochondrial matrix. [[Image:structure.png|300 px|right|thumb|Figure 1: Structure of mitochondrial calcium uniporter colored by functional domain designed in [http://www.pymol.org/ PyMol]. The transmembrane domain is highlighted salmon, the matrix in light cyan, coiled coil in dark violet, and the N-Terminal Domain in slate blue. [https://en.wikipedia.org/wiki/Protein_Data_Bank] [https://www.rcsb.org/structure/6DT0 6DT0] Each domain has a different functional role]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry.<br />
<br />
===Selectivity Filter===<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains <scene name='83/832933/Glu_residues_all/1'>Glu358</scene>, <scene name='83/832933/Trp354/1'>Trp354</scene>, and <scene name='83/832933/Pro359/1'>Pro359</scene> to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/4'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/3'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref> Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12Å wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. <br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Nterm.png|200 px|left|thumb|Figure 2: Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane[https://en.wikipedia.org/wiki/Protein_Data_Bank] [https://www.rcsb.org/structure/6DT0 6DT0]]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8° around its end near the <scene name='83/837230/Nterm/2'>N-Terminal Domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20°, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3195250Sandbox Reserved 16072020-04-21T03:34:38Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a <scene name='83/837230/Ntermsymmetry/1'>dimer of dimers</scene>, described as <scene name='83/837230/Pyramid/2'>tetrameric truncated pyramid</scene>. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> The Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU (Figure 1). The transmembrane domain opens to the surface of the inner mitochondrial membrane, while the soluble domain, the coiled coil and the N-terminal domain reside inside the inner mitochondrial membrane, opening to the mitochondrial matrix. [[Image:structure.png|300 px|right|thumb|Figure 1: Structure of mitochondrial calcium uniporter colored by functional domain designed in [http://www.pymol.org/ PyMol]. The transmembrane domain is highlighted salmon, the matrix in light cyan, coiled coil in dark violet, and the N-Terminal Domain in slate blue. [https://en.wikipedia.org/wiki/Protein_Data_Bank] [https://www.rcsb.org/structure/6DT0 6DT0] Each domain has a different functional role]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry.<br />
<br />
===Selectivity Filter===<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains <scene name='83/832933/Glu_residues_all/1'>Glu358</scene>, <scene name='83/832933/Trp354/1'>Trp354</scene>, and <scene name='83/832933/Pro359/1'>Pro359</scene> to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/4'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/3'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref> Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12Å wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. <br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Nterm.png|200 px|left|thumb|Figure 2: Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane[https://en.wikipedia.org/wiki/Protein_Data_Bank] [https://www.rcsb.org/structure/6DT0 6DT0]]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8° around its end near the <scene name='83/837230/Nterm/2'>N-Terminal Domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20°, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=File:800px-Screen_Shot_2020-03-30_at_4.37.32_PM.png&diff=3195226File:800px-Screen Shot 2020-03-30 at 4.37.32 PM.png2020-04-21T02:56:33Z<p>Elizabeth M. Ratz: </p>
<hr />
<div></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3195224Sandbox Reserved 16072020-04-21T02:48:42Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a <scene name='83/837230/Ntermsymmetry/1'>dimer of dimers</scene>, described as <scene name='83/837230/Pyramid/2'>tetrameric truncated pyramid</scene>. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> The Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU (Figure 1). The transmembrane domain opens to the surface of the inner mitochondrial membrane, while the soluble domain, the coiled coil and the N-terminal domain reside inside the inner mitochondrial membrane, opening to the mitochondrial matrix. [[Image:structure.png|300 px|right|thumb|Figure 1: Structure of mitochondrial calcium uniporter colored by functional domain designed in [http://www.pymol.org/ PyMol]. The transmembrane domain is highlighted salmon, the matrix in light cyan, coiled coil in dark violet, and the N-Terminal Domain in slate blue. [https://en.wikipedia.org/wiki/Protein_Data_Bank] [https://www.rcsb.org/structure/6DT0 6DT0] Each domain has a different functional role]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry.<br />
<br />
===Selectivity Filter===<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains <scene name='83/832933/Glu_residues_all/1'>Glu358</scene>, <scene name='83/832933/Trp354/1'>Trp354</scene>, and <scene name='83/832933/Pro359/1'>Pro359</scene> to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/4'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/3'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref> Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12Å wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. <br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Nterm.png|200 px|left|thumb|Figure 2: Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane[https://en.wikipedia.org/wiki/Protein_Data_Bank] [https://www.rcsb.org/structure/6DT0 6DT0]]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8° around its end near the <scene name='83/837230/Nterm/2'>N-Terminal Domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20°, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3195222Sandbox Reserved 16072020-04-21T02:48:11Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a <scene name='83/837230/Ntermsymmetry/1'>dimer of dimers</scene>, described as <scene name='83/837230/Pyramid/2'>tetrameric truncated pyramid</scene>. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> The Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU (Figure 1). The transmembrane domain opens to the surface of the inner mitochondrial membrane, while the soluble domain, the coiled coil and the N-terminal domain reside inside the inner mitochondrial membrane, opening to the mitochondrial matrix. [[Image:structure.png|300 px|right|thumb|Figure 1: Structure of mitochondrial calcium uniporter colored by functional domain designed in [http://www.pymol.org/ PyMol]. The transmembrane domain is highlighted salmon, the matrix in light cyan, coiled coil in dark violet, and the N-Terminal Domain in slate blue. [https://en.wikipedia.org/wiki/Protein_Data_Bank] [https://www.rcsb.org/structure/6DT0 6DT0] Each domain has a different functional role]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry.<br />
<br />
===Selectivity Filter===<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains <scene name='83/832933/Glu_residues_all/1'>Glu358</scene>, <scene name='83/832933/Trp354/1'>Trp354</scene>, and <scene name='83/832933/Pro359/1'>Pro359</scene> to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/4'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/3'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref> Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12Å wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. <br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Nterm.png|200 px|left|thumb|Figure 2 Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane[https://en.wikipedia.org/wiki/Protein_Data_Bank] [https://www.rcsb.org/structure/6DT0 6DT0]]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8° around its end near the <scene name='83/837230/Nterm/2'>N-Terminal Domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20°, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3195221Sandbox Reserved 16072020-04-21T02:45:38Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a <scene name='83/837230/Ntermsymmetry/1'>dimer of dimers</scene>, described as <scene name='83/837230/Pyramid/2'>tetrameric truncated pyramid</scene>. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> The Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU (figure 2). The transmembrane domain opens to the surface of the inner mitochondrial membrane, while the soluble domain, the coiled coil and the N-terminal domain reside inside the inner mitochondrial membrane, opening to the mitochondrial matrix. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter colored by functional domain designed in [http://www.pymol.org/ PyMol]. The transmembrane domain is highlighted salmon, the matrix in light cyan, coiled coil in dark violet, and the N-Terminal Domain in slate blue. [https://en.wikipedia.org/wiki/Protein_Data_Bank] [https://www.rcsb.org/structure/6DT0 6DT0] Each domain has a different functional role]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry.<br />
<br />
===Selectivity Filter===<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains <scene name='83/832933/Glu_residues_all/1'>Glu358</scene>, <scene name='83/832933/Trp354/1'>Trp354</scene>, and <scene name='83/832933/Pro359/1'>Pro359</scene> to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/4'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/3'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref> Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12Å wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. <br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Nterm.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane[https://en.wikipedia.org/wiki/Protein_Data_Bank] [https://www.rcsb.org/structure/6DT0 6DT0]]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8° around its end near the <scene name='83/837230/Nterm/2'>N-Terminal Domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20°, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3195216Sandbox Reserved 16072020-04-21T02:38:57Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains <scene name='83/832933/Glu_residues_all/1'>Glu358</scene>, <scene name='83/832933/Trp354/1'>Trp354</scene>, and <scene name='83/832933/Pro359/1'>Pro359</scene> to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/4'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/3'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3195214Sandbox Reserved 16072020-04-21T02:37:33Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains <scene name='83/832933/Glu_residues_all/1'>Glu358</scene>, <scene name='83/832933/Trp354/1'>Trp354</scene>, and <scene name='83/832933/Pro359/1'>Pro359</scene> to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/3'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/3'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3195203Sandbox Reserved 16072020-04-21T02:18:23Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains <scene name='83/832933/Glu_residues_all/1'>Glu358</scene>, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/3'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/3'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3195197Sandbox Reserved 16072020-04-21T01:48:55Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/3'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/3'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183511Sandbox Reserved 16072020-04-07T04:52:06Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/3'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/3'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red (A) and Gadolinum (B)]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183508Sandbox Reserved 16072020-04-07T04:48:12Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/3'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/3'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red (A) and Gadolinum (B)]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183507Sandbox Reserved 16072020-04-07T04:46:28Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/3'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red (A) and Gadolinum (B)]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183505Sandbox Reserved 16072020-04-07T04:43:43Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/2'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red (A) and Gadolinum (B)]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183502Sandbox Reserved 16072020-04-07T04:41:47Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref name="Giorgi C">DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red (A) and Gadolinum (B)]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref name="Giorgi C" /><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183501Sandbox Reserved 16072020-04-07T04:39:27Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref>DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref name="Fan C"> DOI: 10.1038/s41586-018-0330-9</ref> Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. <ref name="Fan C" /> The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref name="Fan C" /> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref name="Fan C" /> [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref name="Fan C" /><br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red (A) and Gadolinum (B)]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref>DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref>DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183494Sandbox Reserved 16072020-04-07T04:24:34Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref>DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref> DOI: 10.1038/s41586-018-0330-9</ref> Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. <ref> DOI: 10.1038/s41586-018-0330-9</ref>The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref> DOI: 10.1038/s41586-018-0330-9</ref> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref> DOI: 10.1038/s41586-018-0330-9</ref> [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref> DOI: 10.1038/s41586-018-0330-9</ref><br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red (A) and Gadolinum (B)]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria. <ref>DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria. <ref>DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183493Sandbox Reserved 16072020-04-07T04:22:42Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref>DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. <ref> DOI: 10.1038/s41586-018-0330-9</ref> Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial inner membrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. <ref> DOI: 10.1038/s41586-018-0330-9</ref>The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient.<ref> DOI: 10.1038/s41586-018-0330-9</ref> The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well.<ref> DOI: 10.1038/s41586-018-0330-9</ref> [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix.<ref> DOI: 10.1038/s41586-018-0330-9</ref><br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red (A) and Gadolinum (B)]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria.<br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183490Sandbox Reserved 16072020-04-07T04:20:07Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <ref>DOI 10.1038/s41580-018-0052-8</ref><br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermembrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 1: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient. The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well. [[Image:Symmetry.png|200 px|left|thumb|Figure 2: Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix. <br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <ref name=”Yoo”>PMID:29954988</ref><br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red (A) and Gadolinum (B)]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria.<br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183469Sandbox Reserved 16072020-04-07T04:00:57Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermembrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 1: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient. The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well. [[Image:Symmetry.png|200 px|left|thumb|Figure 2: Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix. <br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/3'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red (A) and Gadolinum (B)]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria.<br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183464Sandbox Reserved 16072020-04-07T03:53:11Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermembrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 1: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient. The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well. [[Image:Symmetry.png|200 px|left|thumb|Figure 2: Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix. <br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca2+ ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca2+ ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red (A) and Gadolinum (B)]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to [https://en.wikipedia.org/wiki/Apoptosis apoptotic] cardiac cell death. Calcium governs [https://en.wikipedia.org/wiki/Cardiac_excitation-contraction_coupling excitation contraction coupling] (EC coupling) of the cardiac muscles, which creates the ATP needed to power the contraction during heart beats. The increase in mitochondrial Ca2+ concentration is essential for the functioning of this muscle contraction. Mitochondrial Ca2+ overload, though, leads to necrotic cardiac cell death and can be targeted with regulation of the MCU. An example of treatment would be with the use of Ru360 (Figure 3) to inhibit the uptake of Ca2+ ions into the mitochondria.<br />
<br />
== Student Contributors ==<br />
<br />
*Holly Rowe<br />
*Lizzy Ratz<br />
*Madi Summers<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183449Sandbox Reserved 16072020-04-07T03:07:53Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermembrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 1: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient. The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well. [[Image:Symmetry.png|200 px|left|thumb|Figure 2: Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix. <br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red (A) and Gadolinum (B)]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183448Sandbox Reserved 16072020-04-07T03:07:14Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermembrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 1: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient. The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well. [[Image:Symmetry.png|200 px|left|thumb|Figure 2: Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix. <br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3: Competitive inhibitors Ruthenium Red and Gadolinum]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183447Sandbox Reserved 16072020-04-07T03:06:53Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermembrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 1: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient. The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well. [[Image:Symmetry.png|200 px|left|thumb|Figure 2: Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix. <br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 3 Competitive inhibitors Ruthenium Red and Gadolinum]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183445Sandbox Reserved 16072020-04-07T03:02:37Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
[https://en.wikipedia.org/wiki/Cryogenic_electron_microscopy Cryogenic electron microscopy] (Cryo-EM) was instrumental in outlining the complete structure of this protein. <br />
<br />
== Structural highlights and mechanism ==<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore with specificity for [https://en.wikipedia.org/wiki/Calcium_signaling Calcium], near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermembrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2: structure of mitochondrial calcium uniporter]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Transmembrane_domain/3'>transmembrane domain</scene> is on the [https://en.wikipedia.org/wiki/Mitochondrion#Structure inner mitochondrial membrane] open to the inner membrane space. The small pore, highly specific for calcium binding is located in <scene name='83/837230/Tm2/1'>transmembrane 2</scene> (TM2) while <scene name='83/837230/Transmembrane_1/2'>transmembrane 1</scene> (TM1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. It is important that the selectivity pore is small, allowing only a dehydrated calcium molecule to interact with the 5 ampier wide glutamate ring. The negative charge of the glutamates carboxyl group attracts the positively charged Calcium ion. Approximately one helical turn below the glutamate ring of the selectivity filter, there is a tyrosine ring coming a 12 ampier wide pore allowing high conductivity. The wider opening allows calcium to rehydrate once they pass the selectivity pore. The domain swapping of TM1 of one subunit with the TM2 of the neighboring subunits allows for a tight packing in the transmembrane connectivity providing flexibility to the uniporter.<br />
===Soluble Domain===<br />
The <scene name='83/837230/Coiled_coil/3'>coiled coil</scene> is the first subsection of the soluble domain, which resides in the inner mitochondrial membrane. The coiled coil functions as the joints of the uniporter, providing flexibility to promote transport of Calcium ions down their concentration gradient. The junction between the transmembrane domain and the coiled coil's flexibility can be attributed to the disordered packing between subunits; subunits A and C adopt different conformations than the B and D subunits, although they superimpose well. [[Image:Symmetry.png|200 px|left|thumb|Symmetry and organization of subunits from looking down into the uniporter from the inner mitochondrial membrane]]When calcium binds to the selectivity pore, the coiled coil swings approximately 8 degrees around its end near the <scene name='83/837230/Coiled_coil/3'>N-terminal domain</scene>. This movement propagates to the top of the transmembrane domain, where the pore is located, about 85 amperes away. The largest displacement triggered by the movement of the coiled coil is in the transmembrane domain, where the coil bends 20 degrees, moving the transmembrane domain further apart. The N-Terminal domain (NTD) is involved in calcium condition. Reorganization in the NTD due to shifts in the coiled coil switch subunits to alter membrane packing causing the interactions between the tyrosines and transmembrane helices. This propagation facilitates a rotamer switch between one pair of tyrosine controlling calcium flow through the pore. The soluble domain is wider than the transmembrane domain, allowing calcium ions to rehydrate and increasing the conductivity of ions through the uniporter into the mitochondrial matrix. <br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183437Sandbox Reserved 16072020-04-07T02:41:02Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
<br />
== Structural highlights and mechanism ==<br />
<br />
[[Image:Bubble_pic.png|300 px|right|thumb|Figure 2 Representation of the calcium fitting into the selectivity pore.]]<br />
<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore, near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermemnrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Selectivity_pore_space_fill/2'>Small pore, highly specific for calcium binding</scene> is located in the <scene name='83/837230/Transmembrane_domain/1'>transmembrane domain</scene>, in TM2 (transmembrane 2) while TM 1 (transmembrane 1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. The domain swapping of TM1 of one subunit tightly packing with the TM2 of the neighboring subunits. <br />
<br />
===Coiled coil===<br />
<br />
===N-terminal Domain===<br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky [https://en.wikipedia.org/wiki/Ryanodine_receptor Ryanodine receptors], causes types [https://en.wikipedia.org/wiki/Type_1_diabetes 1] and [https://en.wikipedia.org/wiki/Type_2_diabetes 2] diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183433Sandbox Reserved 16072020-04-07T02:35:12Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
<br />
== Structural highlights and mechanism ==<br />
<br />
[[Image:Bubble_pic.png|300 px|right|thumb|Figure 2 Representation of the calcium fitting into the selectivity pore.]]<br />
<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore, near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermemnrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Selectivity_pore_space_fill/2'>Small pore, highly specific for calcium binding</scene> is located in the <scene name='83/837230/Transmembrane_domain/1'>transmembrane domain</scene>, in TM2 (transmembrane 2) while TM 1 (transmembrane 1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. The domain swapping of TM1 of one subunit tightly packing with the TM2 of the neighboring subunits. <br />
<br />
===Coiled coil===<br />
<br />
===N-terminal Domain===<br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic [https://en.wikipedia.org/wiki/Beta_cell beta cells] circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183431Sandbox Reserved 16072020-04-07T02:28:39Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
<br />
== Structural highlights and mechanism ==<br />
<br />
[[Image:Bubble_pic.png|300 px|right|thumb|Figure 2 Representation of the calcium fitting into the selectivity pore.]]<br />
<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore, near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermemnrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Selectivity_pore_space_fill/2'>Small pore, highly specific for calcium binding</scene> is located in the <scene name='83/837230/Transmembrane_domain/1'>transmembrane domain</scene>, in TM2 (transmembrane 2) while TM 1 (transmembrane 1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. The domain swapping of TM1 of one subunit tightly packing with the TM2 of the neighboring subunits. <br />
<br />
===Coiled coil===<br />
<br />
===N-terminal Domain===<br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/2'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death <br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183430Sandbox Reserved 16072020-04-07T02:27:36Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
<br />
== Structural highlights and mechanism ==<br />
<br />
[[Image:Bubble_pic.png|300 px|right|thumb|Figure 2 Representation of the calcium fitting into the selectivity pore.]]<br />
<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore, near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermemnrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Selectivity_pore_space_fill/2'>Small pore, highly specific for calcium binding</scene> is located in the <scene name='83/837230/Transmembrane_domain/1'>transmembrane domain</scene>, in TM2 (transmembrane 2) while TM 1 (transmembrane 1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. The domain swapping of TM1 of one subunit tightly packing with the TM2 of the neighboring subunits. <br />
<br />
===Coiled coil===<br />
<br />
===N-terminal Domain===<br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through <scene name='83/832933/H_bond_trp354_glu358/1'>hydrogen bonding</scene> and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death <br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183421Sandbox Reserved 16072020-04-07T02:15:53Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
<br />
== Structural highlights and mechanism ==<br />
<br />
[[Image:Bubble_pic.png|300 px|right|thumb|Figure 2 Representation of the calcium fitting into the selectivity pore.]]<br />
<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore, near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermemnrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Selectivity_pore_space_fill/2'>Small pore, highly specific for calcium binding</scene> is located in the <scene name='83/837230/Transmembrane_domain/1'>transmembrane domain</scene>, in TM2 (transmembrane 2) while TM 1 (transmembrane 1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. The domain swapping of TM1 of one subunit tightly packing with the TM2 of the neighboring subunits. <br />
<br />
===Coiled coil===<br />
<br />
===N-terminal Domain===<br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The <scene name='83/832933/Diameter/1'>diameter</scene> of the carboxyl ring is about 4Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through hydrogen bonding and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death <br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183308Sandbox Reserved 16072020-04-06T20:50:41Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
<br />
== Structural highlights and mechanism ==<br />
<br />
[[Image:Bubble_pic.png|300 px|right|thumb|Figure 2 Representation of the calcium fitting into the selectivity pore.]]<br />
<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore, near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermemnrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Selectivity_pore_space_fill/2'>Small pore, highly specific for calcium binding</scene> is located in the <scene name='83/837230/Transmembrane_domain/1'>transmembrane domain</scene>, in TM2 (transmembrane 2) while TM 1 (transmembrane 1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. The domain swapping of TM1 of one subunit tightly packing with the TM2 of the neighboring subunits. <br />
<br />
===Coiled coil===<br />
<br />
===N-terminal Domain===<br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/2'>Glu358</scene> side chains draw in the positive calcium ion. The diameter of the carboxyl ring is 5Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through hydrogen bonding and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death <br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183307Sandbox Reserved 16072020-04-06T20:46:58Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
<br />
== Structural highlights and mechanism ==<br />
<br />
[[Image:Bubble_pic.png|300 px|right|thumb|Figure 2 Representation of the calcium fitting into the selectivity pore.]]<br />
<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore, near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermemnrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Selectivity_pore_space_fill/2'>Small pore, highly specific for calcium binding</scene> is located in the <scene name='83/837230/Transmembrane_domain/1'>transmembrane domain</scene>, in TM2 (transmembrane 2) while TM 1 (transmembrane 1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. The domain swapping of TM1 of one subunit tightly packing with the TM2 of the neighboring subunits. <br />
<br />
===Coiled coil===<br />
<br />
===N-terminal Domain===<br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the <scene name='83/832933/Glu_358/1'>Glu358</scene> side chains draw in the positive calcium ion. The diameter of the carboxyl ring is 5Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through hydrogen bonding and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death <br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183298Sandbox Reserved 16072020-04-06T20:29:53Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
<br />
== Structural highlights and mechanism ==<br />
<br />
[[Image:Bubble_pic.png|300 px|right|thumb|Figure 2 Representation of the calcium fitting into the selectivity pore.]]<br />
<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore, near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermemnrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Selectivity_pore_space_fill/2'>Small pore, highly specific for calcium binding</scene> is located in the <scene name='83/837230/Transmembrane_domain/1'>transmembrane domain</scene>, in TM2 (transmembrane 2) while TM 1 (transmembrane 1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. The domain swapping of TM1 of one subunit tightly packing with the TM2 of the neighboring subunits. <br />
<br />
===Coiled coil===<br />
<br />
===N-terminal Domain===<br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the Glu side chains draw in the positive calcium ion. The diameter of the carboxyl ring is 5Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through hydrogen bonding and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death <br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3183297Sandbox Reserved 16072020-04-06T20:29:13Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
<br />
== Structural highlights and mechanism ==<br />
<br />
[[Image:Bubble_pic.png|300 px|right|thumb|Figure 2 Representation of the calcium fitting into the selectivity pore.]]<br />
<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore, near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermemnrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Selectivity_pore_space_fill/2'>Small pore, highly specific for calcium binding</scene> is located in the <scene name='83/837230/Transmembrane_domain/1'>transmembrane domain</scene>, in TM2 (transmembrane 2) while TM 1 (transmembrane 1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. The domain swapping of TM1 of one subunit tightly packing with the TM2 of the neighboring subunits. <br />
<br />
===Coiled coil===<br />
<br />
===N-terminal Domain===<br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/2'>TextToBeDisplayed</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the Glu side chains draw in the positive calcium ion. The diameter of the carboxyl ring is 5Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through hydrogen bonding and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death <br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3180392Sandbox Reserved 16072020-03-31T02:07:32Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
Calcium is a very important signaling molecule in the body with many physiological functions including muscle contraction, neuron excitability, cell migration and growth. The mitochondria are important regulators of calcium in the body and the calcium uniporter (MCU) maintains calcium homeostasis within the mitochondria. Calcium moves in one direction from the intermembrane space through the inner mitochondrial membrane into the matrix. The matrix is more negative driven by the respiratory chain which draws calcium in and allows calcium to move down its gradient. <br />
The MCU is a complex. Its MICU1 and MICU2 bind together and associate with EMRE which regulates MCU. The MICU1 and MICU2 act as gatekeepers. EMRE connects the MICU1 and MICU2 sensors to MCU therefore regulating calcium uptake for the protein<br />
<br />
The selectivity pore is an integral part of the protein. This pore contains a group of glutamate with oxygen facing inward forming a carboxylate ring through which calcium enters. This negative carboxylate ring does a good job of pulling the positive calcium into the selectivity pore at the top of the protein.<br />
<br />
== Structural highlights and mechanism ==<br />
<br />
[[Image:Bubble_pic.png|300 px|right|thumb|Figure 2 Representation of the calcium fitting into the selectivity pore.]]<br />
<br />
The MCU is a dimer of dimers, described as tetrameric truncated pyramid. The uniporter has only a single strong binding site located in the selectivity pore, near the surface of the inner mitochondrial membrane. Activity of the uniporter is dependent on membrane potential and calcium concentration. Calcium from the cytoplasm enters the mitochondrial innermemnrane space through the mitochondrial membrane and is passed to the mitochondrial matrix via the MCU. [[Image:structure.png|300 px|right|thumb|Figure 2]]<br />
<br />
===Transmembrane Domain===<br />
The <scene name='83/837230/Selectivity_pore_space_fill/2'>Small pore, highly specific for calcium binding</scene> is located in the <scene name='83/837230/Transmembrane_domain/1'>transmembrane domain</scene>, in TM2 (transmembrane 2) while TM 1 (transmembrane 1) surrounds the pore. The transmembrane domain exhibits four fold rotational symmetry. The domain swapping of TM1 of one subunit tightly packing with the TM2 of the neighboring subunits. <br />
<br />
===Coiled coil===<br />
<br />
===N-terminal Domain===<br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/1'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the Glu side chains draw in the positive calcium ion. The diameter of the carboxyl ring is 5Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through hydrogen bonding and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death <br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3180342Sandbox Reserved 16072020-03-30T21:18:48Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
==Structure==<br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/832933/Selectivity_filter/1'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the Glu side chains draw in the positive calcium ion. The diameter of the carboxyl ring is 5Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through hydrogen bonding and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death <br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3180341Sandbox Reserved 16072020-03-30T20:58:59Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
==Structure==<br />
<br />
===Selectivity Filter===<br />
<br />
The <scene name='83/837222/Selectivity_filter/3'>selectivity filter</scene> contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the Glu side chains draw in the positive calcium ion. The diameter of the carboxyl ring is 5Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through hydrogen bonding and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death <br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=Sandbox_Reserved_1607&diff=3180339Sandbox Reserved 16072020-03-30T20:50:48Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
<scene name='83/837222/Selectivity_filter/3'>Selectivity Filter</scene><br />
<br />
==Structure==<br />
<br />
===Selectivity Filter===<br />
<br />
The selectivity filter contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the Glu side chains draw in the positive calcium ion. The diameter of the carboxyl ring is 5Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through hydrogen bonding and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[[Image:Selectivity_filter.png|400 px|right|thumb|Figure 1]]<br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
[[Image:Screen Shot 2020-03-30 at 4.37.32 PM.png|400 px|left|thumb|Figure 2]]<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
===Heart Failure===<br />
<br />
Calcium overload in the mitochondria of cardiac cells lead to apoptotic cardiac cell death. This large amount of cell death <br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=File:Screen_Shot_2020-03-30_at_4.37.32_PM.png&diff=3180338File:Screen Shot 2020-03-30 at 4.37.32 PM.png2020-03-30T20:37:56Z<p>Elizabeth M. Ratz: </p>
<hr />
<div></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=File:Screen_Shot_2020-03-30_at_4.30.50_PM.png&diff=3180337File:Screen Shot 2020-03-30 at 4.30.50 PM.png2020-03-30T20:32:04Z<p>Elizabeth M. Ratz: </p>
<hr />
<div></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=User:Elizabeth_M._Ratz/Sandbox_1&diff=3180336User:Elizabeth M. Ratz/Sandbox 12020-03-30T20:28:06Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
<scene name='83/837222/Selectivity_filter/3'>Selectivity Filter</scene><br />
<br />
==Structure==<br />
<br />
===Selectivity Filter===<br />
<br />
The selectivity filter contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the Glu side chains draw in the positive calcium ion. The diameter of the carboxyl ring is 5Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through hydrogen bonding and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[[Image:Selectivity_filter.png|400 px|right|thumb|Figure 1]]<br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
===Inhibitors===<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=User:Elizabeth_M._Ratz/Sandbox_1&diff=3177024User:Elizabeth M. Ratz/Sandbox 12020-03-24T02:21:51Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
<scene name='83/837222/Selectivity_filter/3'>Selectivity Filter</scene><br />
<br />
==Structure==<br />
<br />
===Selectivity Filter===<br />
<br />
The selectivity filter contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the Glu side chains draw in the positive calcium ion. The diameter of the carboxyl ring is 5Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through hydrogen bonding and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[[Image:Selectivity_filter.png|400 px|right|thumb|Figure 1]]<br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
== Disease Links==<br />
<br />
===Types 1 and 2 Diabetes===<br />
<br />
Pancreatic beta cells circulate insulin through the body. Glucose initiates signals allowing these cells to break down sugar and release insulin, which is all stimulated by mitochondrial energy metabolism. Calcium homeostasis plays a fundamental role in ATP production supplying energy to this process. Defects in homeostasis of calcium like chronic calcium depletion, caused by leaky Ryanodine receptors, causes types 1 and 2 diabetes through failure of this mechanism. Treatment involves targeting the MCU and MICU1 to open the calcium channel and allow more uptake of calcium ions into the mitochondria.<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=User:Elizabeth_M._Ratz/Sandbox_1&diff=3177009User:Elizabeth M. Ratz/Sandbox 12020-03-24T01:03:41Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
<scene name='83/837222/Selectivity_filter/3'>Selectivity Filter</scene><br />
<br />
==Structure==<br />
<br />
===Selectivity Filter===<br />
<br />
The selectivity filter contains Glu358, Trp354, and Pro359 to allow calcium to pass through the uniporter. The carboxylate oxygen of the Glu side chains draw in the positive calcium ion. The diameter of the carboxyl ring is 5Å, allowing only a dehydrated Ca ion to bind. Trp38, which is directly next to the Glu residues, stabilizes the carbonyl side chains through hydrogen bonding and anion pi interactions. These Trp residues also form stacking interactions with Pro359, which orientate the Glu carboxyl side chains towards the middle of the pore to interact with Ca ions. <br />
<br />
[[Image:Selectivity_filter.png|400 px|right|thumb|Figure 1]]<br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=User:Elizabeth_M._Ratz/Sandbox_1&diff=3163339User:Elizabeth M. Ratz/Sandbox 12020-03-02T20:44:40Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
<scene name='83/837222/Selectivity_filter/3'>Selectivity Filter</scene><br />
<br />
==Structure==<br />
<br />
[[Image:Selectivity_filter.png|400 px|right|thumb|Figure 1]]<br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
<ref name=”Yoo”>PMID:29954988</ref><br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=User:Elizabeth_M._Ratz/Sandbox_1&diff=3163327User:Elizabeth M. Ratz/Sandbox 12020-03-02T20:34:01Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
<scene name='83/837222/Selectivity_filter/3'>Selectivity Filter</scene><br />
<br />
==Structure==<br />
<br />
[[Image:Selectivity_filter.png|400 px|right|thumb|Figure 1]]<br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=User:Elizabeth_M._Ratz/Sandbox_1&diff=3163325User:Elizabeth M. Ratz/Sandbox 12020-03-02T20:32:50Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
<scene name='83/837222/Selectivity_filter/3'>TextToBeDisplayed</scene><br />
<br />
==Structure==<br />
<br />
[[Image:Selectivity_filter.png|400 px|right|thumb|Figure 1]]<br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=User:Elizabeth_M._Ratz/Sandbox_1&diff=3163317User:Elizabeth M. Ratz/Sandbox 12020-03-02T20:28:36Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
<scene name='83/837222/Selectivity_filter/2'>TextToBeDisplayed</scene><br />
<br />
==Structure==<br />
<br />
[[Image:Selectivity_filter.png|400 px|right|thumb|Figure 1]]<br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=User:Elizabeth_M._Ratz/Sandbox_1&diff=3163290User:Elizabeth M. Ratz/Sandbox 12020-03-02T20:07:47Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='6DT0' size='350' frame='true' side='right' caption='Calcium Uniporter 6DT0' scene=’’><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
==Structure==<br />
<br />
[[Image:Selectivity_filter.png|400 px|right|thumb|Figure 1]]<br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=User:Elizabeth_M._Ratz/Sandbox_1&diff=3163285User:Elizabeth M. Ratz/Sandbox 12020-03-02T20:02:55Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
==Structure==<br />
<br />
[[Image:Selectivity_filter.png|400 px|right|thumb|Figure 1]]<br />
<br />
[http://www.rcsb.org/structure/6DT0 Calcium Uniporter Structure]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratzhttps://proteopedia.org/index.php?title=User:Elizabeth_M._Ratz/Sandbox_1&diff=3163269User:Elizabeth M. Ratz/Sandbox 12020-03-02T19:56:15Z<p>Elizabeth M. Ratz: </p>
<hr />
<div>=Mitochondrial Calcium Uniporter=<br />
<StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''><br />
This is a default text for your page '''Elizabeth M. Ratz/Sandbox 1'''. Click above on '''edit this page''' to modify. Be careful with the &lt; and &gt; signs.<br />
You may include any references to papers as in: the use of JSmol in Proteopedia <ref>DOI 10.1002/ijch.201300024</ref> or to the article describing Jmol <ref>PMID:21638687</ref> to the rescue.<br />
<br />
==Introduction==<br />
<br />
==Structure==<br />
<br />
[[Image:Selectivity_filter.png|400 px|right|thumb|Figure 1]]<br />
<br />
== Function ==<br />
<br />
== Disease ==<br />
<br />
== Relevance ==<br />
<br />
== Structural highlights ==<br />
<br />
== Student Contributors ==<br />
<br />
This is a sample scene created with SAT to <scene name="/12/3456/Sample/1">color</scene> by Group, and another to make <scene name="/12/3456/Sample/2">a transparent representation</scene> of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.<br />
<br />
</StructureSection><br />
== References ==<br />
<references/></div>Elizabeth M. Ratz