Proteopedia - User contributions [en]

Eag domain-CNBHD complex of the mouse EAG1

2018-04-15T18:48:14Z

Ariel Ben Bassat: Sendbox moved to Eag domain-CNBHD complex of the mouse EAG1

'''Introduction:''' <Structure load='4LLO' size='300' color='white' frame='true' align='right' caption='testcaption' />

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]] [[Image:Eag+CNBHD.png | thumb ]] [[Image:Ff.jpg | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

----

'''Intracellular domain structure of KCNH1 (mEAG):'''

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)<ref>Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)</ref>. The eag domain regulates the activation and inactivation in unknown mechanism<ref>Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)</ref>. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2)<ref name="y">Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>. The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD<ref name="y" />.
The post CNBHD region has been shown to mediate the regulation of the channel by variety of cell signaling mediators, including phosphorylation, kinases and Ca2+-calmodulin<ref>Cherubini,A.etal.Humanether-a-go-go-relatedgene1channelsarephysically linked to b1 integrins and modulate adhesion-dependent signaling. Mol. Biol. Cell 16, 2972–2983 (2005)</ref>,<ref>Sun,X.X.,Hodge,J.J.,Zhou,Y.,Nguyen,M.&Griffith,L.C.Theeagpotassium channel binds and locally activates calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 10206–10214 (2004)</ref>,<ref>Ziechner,U.etal.Inhibitionofhumanethera`go-gopotassiumchannelsby Ca21/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 273, 1074–1086 (2006)</ref>. The interaction between the eag domain and the post-CNBHD region suggests that KCNH channel regulation through the post-CNBHD region may involve its interaction interface with the eag domain<ref name="y" />.

----

'''Ca2+ Calmodulin (CaM) inhibition:'''

CaM is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells, and the binding of Ca2+ is required for its activation<ref>Stevens FC (1983). "Calmodulin: an introduction". Can. J. Biochem. Cell Biol. 61 (8): 906–10</ref>.
CaM binds EAG in the presence of Ca2+ and inhibits ion conduction<ref>Schonherr R, Lober K, Heinemann SH. Inhibition of human ether a go-go potassium channels by Ca(2+)/calmodulin. EMBO J. 2000;19:3263–3271</ref>,<ref name="x">Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>.
The mechanism is not fully understood. CNBHD – PAS domain complex has 3 CaM contact regions witch form 2 binding sites<ref name="x" />. Two contact regions at the C-terminus of the CNBHD form 2 α-helices that act as a claw to grab the CaM C-lobe. The linker that connect the two lobes of CaM is very flexible thus he can break and allows the hydrophobic core of the CaM N-lobe to bind a helix on the PAS domain<ref>Jonathan R., Whicher Roderick MacKinnon. Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science. 2016 Aug 12; 353(6300): 664–669</ref>.

----

'''Disease:'''

The eag domain-CNBHD complex interface servers as a hot spot for many mutation associates with cancer and LQT2 (hERG).

----

'''Therapeutic potential:'''

The unique intracellular domains of KCNH family may be an orphan receptor.
By finding ligands we may able to regulate these channels and stop these devastating conditions.

----

'''Reference:'''<references />

Eag domain-CNBHD complex of the mouse EAG1

2018-04-15T18:46:26Z

Ariel Ben Bassat:

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T12:32:05Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]] [[Image:Eag+CNBHD.png | thumb ]] [[Image:Ff.jpg | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

----

'''Intracellular domain structure of KCNH1 (mEAG):'''

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)<ref>Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)</ref>. The eag domain regulates the activation and inactivation in unknown mechanism<ref>Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)</ref>. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2)<ref name="y">Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>. The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD<ref name="y" />.
The post CNBHD region has been shown to mediate the regulation of the channel by variety of cell signaling mediators, including phosphorylation, kinases and Ca2+-calmodulin<ref>Cherubini,A.etal.Humanether-a-go-go-relatedgene1channelsarephysically linked to b1 integrins and modulate adhesion-dependent signaling. Mol. Biol. Cell 16, 2972–2983 (2005)</ref>,<ref>Sun,X.X.,Hodge,J.J.,Zhou,Y.,Nguyen,M.&Griffith,L.C.Theeagpotassium channel binds and locally activates calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 10206–10214 (2004)</ref>,<ref>Ziechner,U.etal.Inhibitionofhumanethera`go-gopotassiumchannelsby Ca21/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 273, 1074–1086 (2006)</ref>. The interaction between the eag domain and the post-CNBHD region suggests that KCNH channel regulation through the post-CNBHD region may involve its interaction interface with the eag domain<ref name="y" />.

----

'''Ca2+ Calmodulin (CaM) inhibition:'''

CaM is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells, and the binding of Ca2+ is required for its activation<ref>Stevens FC (1983). "Calmodulin: an introduction". Can. J. Biochem. Cell Biol. 61 (8): 906–10</ref>.
CaM binds EAG in the presence of Ca2+ and inhibits ion conduction<ref>Schonherr R, Lober K, Heinemann SH. Inhibition of human ether a go-go potassium channels by Ca(2+)/calmodulin. EMBO J. 2000;19:3263–3271</ref>,<ref name="x">Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>.
The mechanism is not fully understood. CNBHD – PAS domain complex has 3 CaM contact regions witch form 2 binding sites<ref name="x" />. Two contact regions at the C-terminus of the CNBHD form 2 α-helices that act as a claw to grab the CaM C-lobe. The linker that connect the two lobes of CaM is very flexible thus he can break and allows the hydrophobic core of the CaM N-lobe to bind a helix on the PAS domain<ref>Jonathan R., Whicher Roderick MacKinnon. Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science. 2016 Aug 12; 353(6300): 664–669</ref>.

----

'''Disease:'''

The eag domain-CNBHD complex interface servers as a hot spot for many mutation associates with cancer and LQT2 (hERG).

----

'''Therapeutic potential:'''

The unique intracellular domains of KCNH family may be an orphan receptor.
By finding ligands we may able to regulate these channels and stop these devastating conditions.

----

'''Reference:'''<references />

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T12:30:24Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]] [[Image:Eag+CNBHD.png | thumb ]] [[Image:Ff.jpg | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

'''Intracellular domain structure of KCNH1 (mEAG):'''

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)<ref>Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)</ref>. The eag domain regulates the activation and inactivation in unknown mechanism<ref>Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)</ref>. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2)<ref name="y">Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>. The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD<ref name="y" />.
The post CNBHD region has been shown to mediate the regulation of the channel by variety of cell signaling mediators, including phosphorylation, kinases and Ca2+-calmodulin<ref>Cherubini,A.etal.Humanether-a-go-go-relatedgene1channelsarephysically linked to b1 integrins and modulate adhesion-dependent signaling. Mol. Biol. Cell 16, 2972–2983 (2005)</ref>,<ref>Sun,X.X.,Hodge,J.J.,Zhou,Y.,Nguyen,M.&Griffith,L.C.Theeagpotassium channel binds and locally activates calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 10206–10214 (2004)</ref>,<ref>Ziechner,U.etal.Inhibitionofhumanethera`go-gopotassiumchannelsby Ca21/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 273, 1074–1086 (2006)</ref>. The interaction between the eag domain and the post-CNBHD region suggests that KCNH channel regulation through the post-CNBHD region may involve its interaction interface with the eag domain<ref name="y" />.

'''Ca2+ Calmodulin (CaM) inhibition:'''

CaM is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells, and the binding of Ca2+ is required for its activation<ref>Stevens FC (1983). "Calmodulin: an introduction". Can. J. Biochem. Cell Biol. 61 (8): 906–10</ref>.
CaM binds EAG in the presence of Ca2+ and inhibits ion conduction<ref>Schonherr R, Lober K, Heinemann SH. Inhibition of human ether a go-go potassium channels by Ca(2+)/calmodulin. EMBO J. 2000;19:3263–3271</ref>,<ref name="x">Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>.
The mechanism is not fully understood. CNBHD – PAS domain complex has 3 CaM contact regions witch form 2 binding sites<ref name="x" />. Two contact regions at the C-terminus of the CNBHD form 2 α-helices that act as a claw to grab the CaM C-lobe. The linker that connect the two lobes of CaM is very flexible thus he can break and allows the hydrophobic core of the CaM N-lobe to bind a helix on the PAS domain<ref>Jonathan R., Whicher Roderick MacKinnon. Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science. 2016 Aug 12; 353(6300): 664–669</ref>.

'''Disease:'''

The eag domain-CNBHD complex interface servers as a hot spot for many mutation associates with cancer and LQT2 (hERG).

'''Therapeutic potential:'''

The unique intracellular domains of KCNH family may be an orphan receptor.
By finding ligands we may able to regulate these channels and stop these devastating conditions.

'''Reference:'''<references />

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T12:26:20Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]] [[Image:Eag+CNBHD.png | thumb ]] [[Image:Ff.jpg | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

'''Intracellular domain structure of KCNH1 (mEAG):'''

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)<ref>Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)</ref>. The eag domain regulates the activation and inactivation in unknown mechanism<ref>Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)</ref>. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2)<ref name="y">Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>. The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD<ref name="y" />.
The post CNBHD region has been shown to mediate the regulation of the channel by variety of cell signaling mediators, including phosphorylation, kinases and Ca2+-calmodulin<ref>Cherubini,A.etal.Humanether-a-go-go-relatedgene1channelsarephysically linked to b1 integrins and modulate adhesion-dependent signaling. Mol. Biol. Cell 16, 2972–2983 (2005)</ref>,<ref>Sun,X.X.,Hodge,J.J.,Zhou,Y.,Nguyen,M.&Griffith,L.C.Theeagpotassium channel binds and locally activates calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 10206–10214 (2004)</ref>,<ref>Ziechner,U.etal.Inhibitionofhumanethera`go-gopotassiumchannelsby Ca21/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 273, 1074–1086 (2006)</ref>. The interaction between the eag domain and the post-CNBHD region suggests that KCNH channel regulation through the post-CNBHD region may involve its interaction interface with the eag domain<ref name="y" />.

'''Ca2+ Calmodulin (CaM) inhibition:'''

CaM is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells, and the binding of Ca2+ is required for its activation<ref>Stevens FC (1983). "Calmodulin: an introduction". Can. J. Biochem. Cell Biol. 61 (8): 906–10</ref>.
CaM binds EAG in the presence of Ca2+ and inhibits ion conduction<ref>Schonherr R, Lober K, Heinemann SH. Inhibition of human ether a go-go potassium channels by Ca(2+)/calmodulin. EMBO J. 2000;19:3263–3271</ref>,<ref>Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>.
The mechanism is not fully understood. CNBHD – PAS domain complex has 3 CaM contact regions witch form 2 binding sites<ref>Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>. Two contact regions at the C-terminus of the CNBHD form 2 α-helices that act as a claw to grab the CaM C-lobe. The linker that connect the two lobes of CaM is very flexible thus he can break and allows the hydrophobic core of the CaM N-lobe to bind a helix on the PAS domain<ref>Jonathan R., Whicher Roderick MacKinnon. Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science. 2016 Aug 12; 353(6300): 664–669</ref>.

'''Disease:'''

The eag domain-CNBHD complex interface servers as a hot spot for many mutation associates with cancer and LQT2 (hERG).

'''Therapeutic potential:'''

The unique intracellular domains of KCNH family may be an orphan receptor.
By finding ligands we may able to regulate these channels and stop these devastating conditions.

'''Reference:'''<references />

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T12:24:37Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]] [[Image:Eag+CNBHD.png | thumb ]] [[Image:Ff.jpg | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

'''Intracellular domain structure of KCNH1 (mEAG):'''

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)<ref>Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)</ref>. The eag domain regulates the activation and inactivation in unknown mechanism<ref>Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)</ref>. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2)<ref name="y">Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>. The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD<ref name="y" />.
The post CNBHD region has been shown to mediate the regulation of the channel by variety of cell signaling mediators, including phosphorylation, kinases and Ca2+-calmodulin<ref>Cherubini,A.etal.Humanether-a-go-go-relatedgene1channelsarephysically linked to b1 integrins and modulate adhesion-dependent signaling. Mol. Biol. Cell 16, 2972–2983 (2005)</ref>,<ref>Sun,X.X.,Hodge,J.J.,Zhou,Y.,Nguyen,M.&Griffith,L.C.Theeagpotassium channel binds and locally activates calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 10206–10214 (2004)</ref>,<ref>Ziechner,U.etal.Inhibitionofhumanethera`go-gopotassiumchannelsby Ca21/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 273, 1074–1086 (2006)</ref>. The interaction between the eag domain and the post-CNBHD region suggests that KCNH channel regulation through the post-CNBHD region may involve its interaction interface with the eag domain<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>.

'''Ca2+ Calmodulin (CaM) inhibition:'''

CaM is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells, and the binding of Ca2+ is required for its activation<ref>Stevens FC (1983). "Calmodulin: an introduction". Can. J. Biochem. Cell Biol. 61 (8): 906–10</ref>.
CaM binds EAG in the presence of Ca2+ and inhibits ion conduction<ref>Schonherr R, Lober K, Heinemann SH. Inhibition of human ether a go-go potassium channels by Ca(2+)/calmodulin. EMBO J. 2000;19:3263–3271</ref>,<ref>Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>.
The mechanism is not fully understood. CNBHD – PAS domain complex has 3 CaM contact regions witch form 2 binding sites<ref>Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>. Two contact regions at the C-terminus of the CNBHD form 2 α-helices that act as a claw to grab the CaM C-lobe. The linker that connect the two lobes of CaM is very flexible thus he can break and allows the hydrophobic core of the CaM N-lobe to bind a helix on the PAS domain<ref>Jonathan R., Whicher Roderick MacKinnon. Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science. 2016 Aug 12; 353(6300): 664–669</ref>.

'''Disease:'''

The eag domain-CNBHD complex interface servers as a hot spot for many mutation associates with cancer and LQT2 (hERG).

'''Therapeutic potential:'''

The unique intracellular domains of KCNH family may be an orphan receptor.
By finding ligands we may able to regulate these channels and stop these devastating conditions.

'''Reference:'''<references />

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T12:09:30Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]] [[Image:Eag+CNBHD.png | thumb ]] [[Image:Ff.jpg | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

'''Intracellular domain structure of KCNH1 (mEAG):'''

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)<ref>Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)</ref>. The eag domain regulates the activation and inactivation in unknown mechanism<ref>Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)</ref>. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2)<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>. The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>.
The post CNBHD region has been shown to mediate the regulation of the channel by variety of cell signaling mediators, including phosphorylation, kinases and Ca2+-calmodulin<ref>Cherubini,A.etal.Humanether-a-go-go-relatedgene1channelsarephysically linked to b1 integrins and modulate adhesion-dependent signaling. Mol. Biol. Cell 16, 2972–2983 (2005)</ref>,<ref>Sun,X.X.,Hodge,J.J.,Zhou,Y.,Nguyen,M.&Griffith,L.C.Theeagpotassium channel binds and locally activates calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 10206–10214 (2004)</ref>,<ref>Ziechner,U.etal.Inhibitionofhumanethera`go-gopotassiumchannelsby Ca21/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 273, 1074–1086 (2006)</ref>. The interaction between the eag domain and the post-CNBHD region suggests that KCNH channel regulation through the post-CNBHD region may involve its interaction interface with the eag domain<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>.

'''Ca2+ Calmodulin (CaM) inhibition:'''

CaM is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells, and the binding of Ca2+ is required for its activation<ref>Stevens FC (1983). "Calmodulin: an introduction". Can. J. Biochem. Cell Biol. 61 (8): 906–10</ref>.
CaM binds EAG in the presence of Ca2+ and inhibits ion conduction<ref>Schonherr R, Lober K, Heinemann SH. Inhibition of human ether a go-go potassium channels by Ca(2+)/calmodulin. EMBO J. 2000;19:3263–3271</ref>,<ref>Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>.
The mechanism is not fully understood. CNBHD – PAS domain complex has 3 CaM contact regions witch form 2 binding sites<ref>Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>. Two contact regions at the C-terminus of the CNBHD form 2 α-helices that act as a claw to grab the CaM C-lobe. The linker that connect the two lobes of CaM is very flexible thus he can break and allows the hydrophobic core of the CaM N-lobe to bind a helix on the PAS domain<ref>Jonathan R., Whicher Roderick MacKinnon. Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science. 2016 Aug 12; 353(6300): 664–669</ref>.

'''Disease:'''

The eag domain-CNBHD complex interface servers as a hot spot for many mutation associates with cancer and LQT2 (hERG).

'''Therapeutic potential:'''

The unique intracellular domains of KCNH family may be an orphan receptor.
By finding ligands we may able to regulate these channels and stop these devastating conditions.

'''Reference:'''<references />

File:Ff.jpg

2018-03-29T12:07:46Z

Ariel Ben Bassat:

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T12:07:30Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]] [[Image:Eag+CNBHD.png | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

'''Intracellular domain structure of KCNH1 (mEAG):'''

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)<ref>Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)</ref>. The eag domain regulates the activation and inactivation in unknown mechanism<ref>Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)</ref>. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2)<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>. The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>.
The post CNBHD region has been shown to mediate the regulation of the channel by variety of cell signaling mediators, including phosphorylation, kinases and Ca2+-calmodulin<ref>Cherubini,A.etal.Humanether-a-go-go-relatedgene1channelsarephysically linked to b1 integrins and modulate adhesion-dependent signaling. Mol. Biol. Cell 16, 2972–2983 (2005)</ref>,<ref>Sun,X.X.,Hodge,J.J.,Zhou,Y.,Nguyen,M.&Griffith,L.C.Theeagpotassium channel binds and locally activates calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 10206–10214 (2004)</ref>,<ref>Ziechner,U.etal.Inhibitionofhumanethera`go-gopotassiumchannelsby Ca21/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 273, 1074–1086 (2006)</ref>. The interaction between the eag domain and the post-CNBHD region suggests that KCNH channel regulation through the post-CNBHD region may involve its interaction interface with the eag domain<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>.

'''Ca2+ Calmodulin (CaM) inhibition:'''

CaM is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells, and the binding of Ca2+ is required for its activation<ref>Stevens FC (1983). "Calmodulin: an introduction". Can. J. Biochem. Cell Biol. 61 (8): 906–10</ref>.
CaM binds EAG in the presence of Ca2+ and inhibits ion conduction<ref>Schonherr R, Lober K, Heinemann SH. Inhibition of human ether a go-go potassium channels by Ca(2+)/calmodulin. EMBO J. 2000;19:3263–3271</ref>,<ref>Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>.
The mechanism is not fully understood. CNBHD – PAS domain complex has 3 CaM contact regions witch form 2 binding sites<ref>Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>. Two contact regions at the C-terminus of the CNBHD form 2 α-helices that act as a claw to grab the CaM C-lobe. The linker that connect the two lobes of CaM is very flexible thus he can break and allows the hydrophobic core of the CaM N-lobe to bind a helix on the PAS domain<ref>Jonathan R., Whicher Roderick MacKinnon. Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science. 2016 Aug 12; 353(6300): 664–669</ref>.

'''Disease:'''

The eag domain-CNBHD complex interface servers as a hot spot for many mutation associates with cancer and LQT2 (hERG).

'''Therapeutic potential:'''

The unique intracellular domains of KCNH family may be an orphan receptor.
By finding ligands we may able to regulate these channels and stop these devastating conditions.

'''Reference:'''<references />

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T12:03:04Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]] [[Image:Eag+CNBHD.png | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

'''Intracellular domain structure of KCNH1 (mEAG):'''

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)<ref>Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)</ref>. The eag domain regulates the activation and inactivation in unknown mechanism<ref>Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)</ref>. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2)<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>. The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>.
The post CNBHD region has been shown to mediate the regulation of the channel by variety of cell signaling mediators, including phosphorylation, kinases and Ca2+-calmodulin<ref>Cherubini,A.etal.Humanether-a-go-go-relatedgene1channelsarephysically linked to b1 integrins and modulate adhesion-dependent signaling. Mol. Biol. Cell 16, 2972–2983 (2005)</ref>,<ref>Sun,X.X.,Hodge,J.J.,Zhou,Y.,Nguyen,M.&Griffith,L.C.Theeagpotassium channel binds and locally activates calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 10206–10214 (2004)</ref>,<ref>Ziechner,U.etal.Inhibitionofhumanethera`go-gopotassiumchannelsby Ca21/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 273, 1074–1086 (2006)</ref>. The interaction between the eag domain and the post-CNBHD region suggests that KCNH channel regulation through the post-CNBHD region may involve its interaction interface with the eag domain<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>.

'''Ca2+ Calmodulin (CaM) inhibition:'''

CaM is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells, and the binding of Ca2+ is required for its activation<ref>Stevens FC (1983). "Calmodulin: an introduction". Can. J. Biochem. Cell Biol. 61 (8): 906–10</ref>.
CaM binds EAG in the presence of Ca2+ and inhibits ion conduction<ref>Schonherr R, Lober K, Heinemann SH. Inhibition of human ether a go-go potassium channels by Ca(2+)/calmodulin. EMBO J. 2000;19:3263–3271</ref>,<ref>Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>.
The mechanism is not fully understood. CNBHD – PAS domain complex has 3 CaM contact regions witch form 2 binding sites<ref>Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>. Two contact regions at the C-terminus of the CNBHD form 2 α-helices that act as a claw to grab the CaM C-lobe. The linker that connect the two lobes of CaM is very flexible thus he can break and allows the hydrophobic core of the CaM N-lobe to bind a helix on the PAS domain<ref>Jonathan R., Whicher Roderick MacKinnon. Structure of the voltage-gated K+ channel Eag1 reveals an alternative voltage sensing mechanism. Science. 2016 Aug 12; 353(6300): 664–669</ref>.

'''Reference:'''<references />

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T12:02:12Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]] [[Image:Eag+CNBHD.png | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

'''Intracellular domain structure of KCNH1 (mEAG):'''

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)<ref>Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)</ref>. The eag domain regulates the activation and inactivation in unknown mechanism<ref>Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)</ref>. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2)<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>. The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>.
The post CNBHD region has been shown to mediate the regulation of the channel by variety of cell signaling mediators, including phosphorylation, kinases and Ca2+-calmodulin<ref>Cherubini,A.etal.Humanether-a-go-go-relatedgene1channelsarephysically linked to b1 integrins and modulate adhesion-dependent signaling. Mol. Biol. Cell 16, 2972–2983 (2005)</ref>,<ref>Sun,X.X.,Hodge,J.J.,Zhou,Y.,Nguyen,M.&Griffith,L.C.Theeagpotassium channel binds and locally activates calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 10206–10214 (2004)</ref>,<ref>Ziechner,U.etal.Inhibitionofhumanethera`go-gopotassiumchannelsby Ca21/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 273, 1074–1086 (2006)</ref>. The interaction between the eag domain and the post-CNBHD region suggests that KCNH channel regulation through the post-CNBHD region may involve its interaction interface with the eag domain<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>.

'''Ca2+ Calmodulin (CaM) inhibition:'''

CaM is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells, and the binding of Ca2+ is required for its activation<ref>Stevens FC (1983). "Calmodulin: an introduction". Can. J. Biochem. Cell Biol. 61 (8): 906–10</ref>.
CaM binds EAG in the presence of Ca2+ and inhibits ion conduction<ref>Schonherr R, Lober K, Heinemann SH. Inhibition of human ether a go-go potassium channels by Ca(2+)/calmodulin. EMBO J. 2000;19:3263–3271</ref>,<ref>Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>.
The mechanism is not fully understood. CNBHD – PAS domain complex has 3 CaM contact regions witch form 2 binding sites<ref>Ziechner U, et al. Inhibition of human ether a go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 2006;273:1074–1086</ref>. Two contact regions at the C-terminus of the CNBHD form 2 α-helices that act as a claw to grab the CaM C-lobe. The linker that connect the two lobes of CaM is very flexible thus he can break and allows the hydrophobic core of the CaM N-lobe to bind a helix on the PAS domain14.

'''Reference:'''<references />

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T11:38:32Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]] [[Image:Eag+CNBHD.png | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

'''Intracellular domain structure of KCNH1 (mEAG):'''

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)<ref>Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)</ref>. The eag domain regulates the activation and inactivation in unknown mechanism<ref>Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)</ref>. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2)<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>. The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>.
The post CNBHD region has been shown to mediate the regulation of the channel by variety of cell signaling mediators, including phosphorylation, kinases and Ca2+-calmodulin<ref>Cherubini,A.etal.Humanether-a-go-go-relatedgene1channelsarephysically linked to b1 integrins and modulate adhesion-dependent signaling. Mol. Biol. Cell 16, 2972–2983 (2005)</ref>,<ref>Sun,X.X.,Hodge,J.J.,Zhou,Y.,Nguyen,M.&Griffith,L.C.Theeagpotassium channel binds and locally activates calcium/calmodulin-dependent protein kinase II. J. Biol. Chem. 279, 10206–10214 (2004)</ref>,<ref>Ziechner,U.etal.Inhibitionofhumanethera`go-gopotassiumchannelsby Ca21/calmodulin binding to the cytosolic N- and C-termini. FEBS J. 273, 1074–1086 (2006)</ref>. The interaction between the eag domain and the post-CNBHD region suggests that KCNH channel regulation through the post-CNBHD region may involve its interaction interface with the eag domain<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>.

'''Ca2+ Calmodulin (CaM) inhibition:'''

CaM is a multifunctional intermediate calcium-binding messenger protein expressed in all eukaryotic cells, and the binding of Ca2+ is required for its activation13.
CaM binds EAG in the presence of Ca2+ and inhibits ion conduction11,12.
The mechanism is not fully understood. CNBHD – PAS domain complex has 3 CaM contact regions witch form 2 binding sites12. Two contact regions at the C-terminus of the CNBHD form 2 α-helices that act as a claw to grab the CaM C-lobe. The linker that connect the two lobes of CaM is very flexible thus he can break and allows the hydrophobic core of the CaM N-lobe to bind a helix on the PAS domain14.

'''Reference:'''<references />

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T11:23:40Z

Ariel Ben Bassat:

File:Eag+CNBHD.png

2018-03-29T11:22:23Z

Ariel Ben Bassat:

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T11:19:36Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

'''Intracellular domain structure of KCNH1 (mEAG):'''

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)<ref>Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)</ref>. The eag domain regulates the activation and inactivation in unknown mechanism<ref>Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)</ref>. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2). The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>.

'''Reference:'''<references />

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T10:50:19Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

'''Intracellular domain structure of KCNH1 (mEAG):'''

KCNH channels have two intracellular domains that provide the unique properties of regulation and gating to this channel family. The CNBHD (residues 517-698) located on the C-terminus, however dose not bind cyclic nucleotides and regulates gating in unknown mechanism. The eag domain (residues 1-136) composed of a PAS domain (110 amino acid) and highly conserved PAS-cap (25 amino acid)<ref>Morais Cabral, J. H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998)</ref>. The eag domain regulates the activation and inactivation in unknown mechanism<ref>Gustina, A. S. & Trudeau, M. C. HERG potassium channel regulation by the N-terminal eag domain. Cell. Signal. 24, 1592–1598 (2012)</ref>. The interface between the eag domain and the CNBHD is with an average buried solvent-accessible surface area of ~ (1,400 A ̊2)<ref>Haitin, Y., A.E. Carlson, and W.N. Zagotta. 2013. The structural mechanism of KCNH-channel regulation by the eag domain. Nature</ref>. The interface consists of three sub-regions: (1) the intrinsic ligand motif of the CNBHD interacts with the aB-helix in the PAS domain; (2) the bA and bB strands of the PAS domain interact with the post-CNBHD segment of the CNBHD; and (3) an amphipathic helix (aCAP) in the PAS-cap domain forms an inter- action with the b-roll of the CNBHD7.

'''Reference:'''<references />

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T10:22:30Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]] [[Image:KCNH1.png | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

'''Reference:'''<references />

File:KCNH1.png

2018-03-29T10:09:27Z

Ariel Ben Bassat:

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T10:04:05Z

Ariel Ben Bassat:

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential.[[Image:KCNH_family_tree.png | thumb ]]
They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)<ref>Sanguinetti, M. C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).</ref>, epilepsy<ref>Zhang, X. et al. Deletion of the potassium channel Kv12.2 causes hippocampal hyperexcitability and epilepsy. Nature Neurosci. 13, 1056–1058 (2010).</ref>, schizophrenia<ref>Huffaker, S. J. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nature Med. 15, 509–518 (2009).</ref> and cancer<ref> Camacho, J. Ether a` go-go potassium channels and cancer. Cancer Lett. 233, 1–9 (2006).</ref>. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels.
The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).

'''Reference:'''<references />

File:KCNH family tree.png

2018-03-29T08:21:05Z

Ariel Ben Bassat:

Eag domain-CNBHD complex of the mouse EAG1

2018-03-29T08:17:27Z

Ariel Ben Bassat: New page: '''Introduction:''' The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential. They pla...

'''Introduction:'''

The KCNH voltage-gated channels are transmembrane channels highly selective for potassium and sensitive to voltage changes in the cells’ membrane potential. They play a crucial roles in repolarization of cells to their resting state and in various diseases such as cardiac long QT syndrome type 2 (LQT2)1, epilepsy2, schizophrenia3 and cancer4. The KCNH channels family has unique intracellular domains that distinguish them from other voltage-gated channels. The amino terminal contains an eag domain and the C-terminus contains a cyclic nucleotide binding homology domain (CNBDH).