Sandbox Reserved 1649: Difference between revisions

Line 31:

'''Amino-terminal domain (ATD)'''

The '''ATD''' is constituted by the '''first 383 amino acids''' of NR2A. ATD is an alpha and beta protein class. Its structure is '''bilobed''' and forms a clam-shell like structure which consists in two lobes linked by a flexible hinge region defining a central groove. <ref name="ATD clamshell">DOI 10.1038/nsmb.2522</ref> Zn2+ may insert between 2 lobes and induces closure of channel by changing conformation of ATD. Zn increases affinity of glutamate on the LBD which reminds the desensitization of [https://en.wikipedia.org/wiki/AMPA_receptor AMPA] and [https://en.wikipedia.org/wiki/Kainate_receptor Kainate receptor]. <ref name="Zn">DOI 10.1016/s0896-6273(00)00163-x</ref> <ref name="ATD RE">DOI 10.1051/medsci/201026165</ref>

The '''ATD''' is constituted by the '''first 383 amino acids''' of NR2A. ATD is an alpha and beta protein class. Its structure is '''bilobed''' and forms a clam-shell like structure which consists in two lobes linked by a flexible hinge region defining a central groove. <ref name="ATD clamshell">DOI 10.1038/nsmb.2522</ref> Zn2+ may insert between 2 lobes and induces '''closure of channel''' by changing conformation of ATD. Zn increases affinity of glutamate on the LBD which reminds the desensitization of [https://en.wikipedia.org/wiki/AMPA_receptor AMPA] and [https://en.wikipedia.org/wiki/Kainate_receptor Kainate receptor]. <ref name="Zn">DOI 10.1016/s0896-6273(00)00163-x</ref> <ref name="ATD RE">DOI 10.1051/medsci/201026165</ref>

ATD allows to modulate NMDA receptor. The difference between various NR2 is mainly regulated by ATD. Indeed, the diversity of ATD can modulate traffic in endoplasmic reticulum and then affect the localization of NMDAr. ATD of NR2A increases glutamate affinity, controls channel’s opening with high probability and opens duration, controls glutamate deactivation time course.<ref name="ATD function">DOI 10.1523/JNEUROSCI.1365-09.2009</ref>

'''Ligand binding domain (LBD)'''

LBD is constituted of two domains S1 (located juste upstream M1 transmembrane domain) and S2 and has affinity for <scene name='86/868182/Lbd/3'>glutamate</scene> or sometimes [https://en.wikipedia.org/wiki/Glycine Glycine]. Positive charge of amino-group of the agonist binds to negative charges residue of the pocket D731. In [https://proteopedia.org/wiki/index.php/Glutamate_receptor_%28GluA2%29 GlurR], negative charge amino acid is a E731 and is able to form [https://en.wikipedia.org/wiki/Salt_bridge salt bridge] with agonist. In NR2A D731 (which corresponds to <scene name='86/868182/D213/3'>D213</scene>) is not able to do [https://en.wikipedia.org/wiki/Salt_bridge salt bridge] with amino group because [https://fr.wikipedia.org/wiki/Acide_aspartique aspartate] is one methylene lacking to do it. Amino group of agonist is stabilized by water mediated hydrogen bonds to amino acid Y761 (which corresponds to <scene name='86/868182/Y243/2'>Y243</scene>) and E413 (which correspond to <scene name='86/868182/E14/3'>E14</scene>).<scene name='86/868182/Y243_et_e14/2'>Click here if you want to see E14 and Y243 together</scene>. The high affinity for glutamate agonist may be because of Van der Walls contact between γ-carboxylate group of glutamate and Y730 of S2 domain which is conserved in NR2 protein.<ref name="LBD">DOI 10.1038/nature04089</ref> Amino-group of glutamate also interacts with <scene name='86/868182/T114/3'>T114</scene> and <scene name='86/868182/S112/2'>S112</scene>. <scene name='86/868182/T114_et_s112/2'>(T114 and S112 together).</scene>

LBD is constituted of '''two domains S1''' (located juste upstream M1 transmembrane domain) '''and S2''' and has affinity for <scene name='86/868182/Lbd/3'>glutamate</scene> or sometimes [https://en.wikipedia.org/wiki/Glycine Glycine]. Positive charge of amino-group of the agonist binds to negative charges residue of the pocket D731. In [https://proteopedia.org/wiki/index.php/Glutamate_receptor_%28GluA2%29 GlurR], negative charge amino acid is a E731 and is able to form [https://en.wikipedia.org/wiki/Salt_bridge salt bridge] with agonist. In NR2A D731 (which corresponds to <scene name='86/868182/D213/3'>D213</scene>) is not able to do [https://en.wikipedia.org/wiki/Salt_bridge salt bridge] with amino group because [https://fr.wikipedia.org/wiki/Acide_aspartique aspartate] is one methylene lacking to do it. Amino group of agonist is stabilized by water mediated hydrogen bonds to amino acid Y761 (which corresponds to <scene name='86/868182/Y243/2'>Y243</scene>) and E413 (which correspond to <scene name='86/868182/E14/3'>E14</scene>).<scene name='86/868182/Y243_et_e14/2'>Click here if you want to see E14 and Y243 together</scene>. The high affinity for glutamate agonist may be because of Van der Walls contact between γ-carboxylate group of glutamate and Y730 of S2 domain which is conserved in NR2 protein.<ref name="LBD">DOI 10.1038/nature04089</ref> Amino-group of glutamate also interacts with <scene name='86/868182/T114/3'>T114</scene> and <scene name='86/868182/S112/2'>S112</scene>. <scene name='86/868182/T114_et_s112/2'>(T114 and S112 together).</scene>

On the other hand, <scene name='86/868182/Interact_with_nr1/1'>certain amino acids</scene> from this domain interact with NR1 (see NR1/NR2A complex part).

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'''Transmembrane domain'''

The transmembrane domain is organized into 4 parts (from M1 to M4). M1 connects the N-terminal domain to M2. M2 forms a reentrant loop contributing to the pore. The S1 segment of the N-terminal domain intertwines with the S2 segment of the GlnBP-type domain in the extracellular loop M3 - M4 to form the glutamate binding pocket. On the other hand, desensitization of NMDA receptors is affected by residues near or inside the binding pocket as well as by residues in M2 that line the pore and the M3 loop - M4 is not responsible for the specificity of the NR2 subunit of glycine independent desensitization. <ref name="transmembrane domain">DOI 10.1016/S0896-6273(00)80459-6</ref>

The transmembrane domain is organized into '''4 parts''' (from M1 to M4). '''M1''' connects the N-terminal domain to M2. '''M2''' forms a reentrant loop contributing to the pore. The '''S1''' segment of the N-terminal domain '''intertwines with the S2 segment''' of the GlnBP-type domain in the extracellular loop '''M3 - M4''' to form the '''glutamate binding pocket'''. On the other hand, desensitization of NMDA receptors is affected by residues near or inside the binding pocket as well as by residues in M2 that line the pore and the M3 loop - M4 is not responsible for the specificity of the NR2 subunit of glycine independent desensitization. <ref name="transmembrane domain">DOI 10.1016/S0896-6273(00)80459-6</ref>

M2 loop is a channel-lining loop and located in transmembrane domain. Two [https://en.wikipedia.org/wiki/Asparagine asparagines] are located on N site of the domain and block Mg2+ and are permeable of Ca2+ <ref name="M2loop">DOI 10.3390/ijms21041538</ref>

Structurally, there is a small loop of 150 amino acids between M3 and M4. Ethanol acts as an inhibitor on NMDAr. [https://en.wikipedia.org/wiki/Phenylalanine phenylalanine] at position 639 in the M3 part of the transmembrane domain of NR2A interacts with the latter.<ref name="ethanol inhibition">DOI 10.1074 / jbc.M102800200</ref>

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'''CTD'''

CTD domain is the less conserved of the NR2 domains. Like ATD, it allows different localization of NMDAr thanks to reticulum endoplasmic trafficking. It is indispensable for receptor surface dynamic and activation of specific signaling. CTD phosphorylation can modulate NMDAr, for instance it is useful for endocytosis during glutamate binding on LBD. <ref name="M2loop"/>

CTD domain is the '''less conserved''' of the NR2 domains. Like ATD, it allows different localization of NMDAr thanks to reticulum endoplasmic trafficking. It is indispensable for receptor surface dynamic and activation of specific signaling. CTD phosphorylation can modulate NMDAr, for instance it is useful for endocytosis during glutamate binding on LBD. <ref name="M2loop"/>

== Regulation ==

A high quantity of stress can lead to the overactivation of NMDA receptors. Therefore, a regulation can occur on NMDA receptors in order to avoid any neuronal injury. <ref name="Structural Rearrangements of NR1/NR2A NMDA Receptors during Allosteric Inhibition">DOI 10.1016/j.neuron.2010.08.011</ref> This very important regulation can act at the level of NR2A subunit.

A '''high quantity of stress''' can lead to the '''overactivation''' of NMDA receptors. Therefore, a regulation can occur on NMDA receptors in order to avoid any neuronal injury. <ref name="Structural Rearrangements of NR1/NR2A NMDA Receptors during Allosteric Inhibition">DOI 10.1016/j.neuron.2010.08.011</ref> This very important regulation can act at the level of NR2A subunit.

For now, scientists know that regulation can occur in several ways: either a modification directly affects the functioning of the receptor, or the quantity of receptors at the surface of the neuron by modifying NR2A itself or not.

Line 58:

'''• Inhibition by Zn2+ '''

Zn2+ exercises a control on the functioning of NR2A. Zn2+ is considered to be an endogenous inhibitor of NMDA receptors. Indeed, the NTD of NR2A subunit forms a binding site for Zn2+.

Zn2+ exercises a control on the functioning of NR2A. Zn2+ is considered to be an '''endogenous inhibitor''' of NMDA receptors. Indeed, the NTD of NR2A subunit forms a binding site for Zn2+.

The binding of Zn2+ on NR2A generates an allosteric modulation of NMDA receptor, leading to its closure. The molecular mechanisms by which the NTD can communicate the inhibitory change of conformation to the rest of the receptor is still unknown. Nevertheless, the LBD was identified as a major intermediate between the NTD to the channel gate.

Line 71:

'''• Inhibition by palmitoylation directly on NR2A'''

NR2A has two distinct consensus cysteine clusters in its C-terminal region, which are susceptible to be [https://en.wikipedia.org/wiki/Palmitoylation palmitoylated].

NR2A has '''two distinct consensus cysteine clusters''' in its C-terminal region, which are susceptible to be [https://en.wikipedia.org/wiki/Palmitoylation palmitoylated].

If the first cluster is palmitoylated, the activity of some tyrosine kinases is increased. Their phosphorylations lead to enhanced stability of NMDA receptors on the cell surface, but also ensure their proper surface delivery from the Golgi apparatus. In contrast, depalmitoylation of this cluster decreases the surface NMDA receptors, because there are less stably associated with the plasma membrane.

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@@ Line 31: / Line 31: @@
 '''Amino-terminal domain (ATD)'''
-The '''ATD''' is constituted by the '''first 383 amino acids''' of NR2A. ATD is an alpha and beta protein class. Its structure is '''bilobed''' and forms a clam-shell like structure which consists in two lobes linked by a flexible hinge region defining a central groove. <ref name="ATD clamshell">DOI 10.1038/nsmb.2522</ref> Zn2+ may insert between 2 lobes and induces closure of channel by changing conformation of ATD. Zn increases affinity of glutamate on the LBD which reminds the desensitization of [https://en.wikipedia.org/wiki/AMPA_receptor AMPA] and [https://en.wikipedia.org/wiki/Kainate_receptor Kainate receptor].  <ref name="Zn">DOI 10.1016/s0896-6273(00)00163-x</ref> <ref name="ATD RE">DOI 10.1051/medsci/201026165</ref>
+The '''ATD''' is constituted by the '''first 383 amino acids''' of NR2A. ATD is an alpha and beta protein class. Its structure is '''bilobed''' and forms a clam-shell like structure which consists in two lobes linked by a flexible hinge region defining a central groove. <ref name="ATD clamshell">DOI 10.1038/nsmb.2522</ref> Zn2+ may insert between 2 lobes and induces '''closure of channel''' by changing conformation of ATD. Zn increases affinity of glutamate on the LBD which reminds the desensitization of [https://en.wikipedia.org/wiki/AMPA_receptor AMPA] and [https://en.wikipedia.org/wiki/Kainate_receptor Kainate receptor].  <ref name="Zn">DOI 10.1016/s0896-6273(00)00163-x</ref> <ref name="ATD RE">DOI 10.1051/medsci/201026165</ref>
 ATD allows to modulate NMDA receptor. The difference between various NR2 is mainly regulated by ATD. Indeed, the diversity of ATD can modulate traffic in endoplasmic reticulum and then affect the localization of NMDAr. ATD of NR2A increases glutamate affinity, controls channel’s opening with high probability and opens duration, controls glutamate deactivation time course.<ref name="ATD function">DOI 10.1523/JNEUROSCI.1365-09.2009</ref>
 '''Ligand binding domain (LBD)'''
-LBD is constituted of two domains S1 (located juste upstream M1 transmembrane domain) and S2 and has affinity for <scene name='86/868182/Lbd/3'>glutamate</scene> or sometimes [https://en.wikipedia.org/wiki/Glycine Glycine]. Positive charge of amino-group of the agonist binds to negative charges residue of the pocket D731. In [https://proteopedia.org/wiki/index.php/Glutamate_receptor_%28GluA2%29 GlurR], negative charge amino acid is a E731 and is able to form [https://en.wikipedia.org/wiki/Salt_bridge salt bridge] with agonist. In NR2A D731 (which corresponds to <scene name='86/868182/D213/3'>D213</scene>) is not able to do [https://en.wikipedia.org/wiki/Salt_bridge salt bridge] with amino group because [https://fr.wikipedia.org/wiki/Acide_aspartique aspartate] is one methylene lacking to do it. Amino group of agonist is stabilized by water mediated hydrogen bonds to amino acid Y761 (which corresponds to <scene name='86/868182/Y243/2'>Y243</scene>) and E413 (which correspond to <scene name='86/868182/E14/3'>E14</scene>).<scene name='86/868182/Y243_et_e14/2'>Click here if you want to see E14 and Y243 together</scene>. The high affinity for glutamate agonist may be because of Van der Walls contact between γ-carboxylate group of glutamate and Y730 of S2 domain which is conserved in NR2 protein.<ref name="LBD">DOI 10.1038/nature04089</ref> Amino-group of glutamate also interacts with <scene name='86/868182/T114/3'>T114</scene> and <scene name='86/868182/S112/2'>S112</scene>. <scene name='86/868182/T114_et_s112/2'>(T114 and S112 together).</scene>
+LBD is constituted of '''two domains S1''' (located juste upstream M1 transmembrane domain) '''and S2''' and has affinity for <scene name='86/868182/Lbd/3'>glutamate</scene> or sometimes [https://en.wikipedia.org/wiki/Glycine Glycine]. Positive charge of amino-group of the agonist binds to negative charges residue of the pocket D731. In [https://proteopedia.org/wiki/index.php/Glutamate_receptor_%28GluA2%29 GlurR], negative charge amino acid is a E731 and is able to form [https://en.wikipedia.org/wiki/Salt_bridge salt bridge] with agonist. In NR2A D731 (which corresponds to <scene name='86/868182/D213/3'>D213</scene>) is not able to do [https://en.wikipedia.org/wiki/Salt_bridge salt bridge] with amino group because [https://fr.wikipedia.org/wiki/Acide_aspartique aspartate] is one methylene lacking to do it. Amino group of agonist is stabilized by water mediated hydrogen bonds to amino acid Y761 (which corresponds to <scene name='86/868182/Y243/2'>Y243</scene>) and E413 (which correspond to <scene name='86/868182/E14/3'>E14</scene>).<scene name='86/868182/Y243_et_e14/2'>Click here if you want to see E14 and Y243 together</scene>. The high affinity for glutamate agonist may be because of Van der Walls contact between γ-carboxylate group of glutamate and Y730 of S2 domain which is conserved in NR2 protein.<ref name="LBD">DOI 10.1038/nature04089</ref> Amino-group of glutamate also interacts with <scene name='86/868182/T114/3'>T114</scene> and <scene name='86/868182/S112/2'>S112</scene>. <scene name='86/868182/T114_et_s112/2'>(T114 and S112 together).</scene>
 On the other hand, <scene name='86/868182/Interact_with_nr1/1'>certain amino acids</scene> from this domain interact with NR1 (see NR1/NR2A complex part).
@@ Line 42: / Line 42: @@
 '''Transmembrane domain'''
-The transmembrane domain is organized into 4 parts (from M1 to M4). M1 connects the N-terminal domain to M2. M2 forms a reentrant loop contributing to the pore. The S1 segment of the N-terminal domain intertwines with the S2 segment of the GlnBP-type domain in the extracellular loop M3 - M4 to form the glutamate binding pocket. On the other hand, desensitization of NMDA receptors is affected by residues near or inside the binding pocket as well as by residues in M2 that line the pore and the M3 loop - M4 is not responsible for the specificity of the NR2 subunit of glycine independent desensitization. <ref name="transmembrane domain">DOI 10.1016/S0896-6273(00)80459-6</ref>
+The transmembrane domain is organized into '''4 parts''' (from M1 to M4). '''M1''' connects the N-terminal domain to M2. '''M2''' forms a reentrant loop contributing to the pore. The '''S1''' segment of the N-terminal domain '''intertwines with the S2 segment''' of the GlnBP-type domain in the extracellular loop '''M3 - M4''' to form the '''glutamate binding pocket'''. On the other hand, desensitization of NMDA receptors is affected by residues near or inside the binding pocket as well as by residues in M2 that line the pore and the M3 loop - M4 is not responsible for the specificity of the NR2 subunit of glycine independent desensitization. <ref name="transmembrane domain">DOI 10.1016/S0896-6273(00)80459-6</ref>
 M2 loop is a channel-lining loop and located in transmembrane domain. Two [https://en.wikipedia.org/wiki/Asparagine asparagines] are located on N site of the domain and block Mg2+ and are permeable of Ca2+ <ref name="M2loop">DOI 10.3390/ijms21041538</ref>
 Structurally, there is a small loop of 150 amino acids between M3 and M4. Ethanol acts as an inhibitor on NMDAr. [https://en.wikipedia.org/wiki/Phenylalanine phenylalanine] at position 639 in the M3 part of the transmembrane domain of NR2A interacts with the latter.<ref name="ethanol inhibition">DOI 10.1074 / jbc.M102800200</ref>
@@ Line 48: / Line 48: @@
 '''CTD'''
-CTD domain is the less conserved of the NR2 domains. Like ATD, it allows different localization of NMDAr thanks to reticulum endoplasmic trafficking. It is indispensable for receptor surface dynamic and activation of specific signaling. CTD phosphorylation can modulate NMDAr, for instance it is useful for endocytosis during glutamate binding on LBD. <ref name="M2loop"/>
+CTD domain is the '''less conserved''' of the NR2 domains. Like ATD, it allows different localization of NMDAr thanks to reticulum endoplasmic trafficking. It is indispensable for receptor surface dynamic and activation of specific signaling. CTD phosphorylation can modulate NMDAr, for instance it is useful for endocytosis during glutamate binding on LBD. <ref name="M2loop"/>
 == Regulation ==
-A high quantity of stress can lead to the overactivation of NMDA receptors. Therefore, a regulation can occur on NMDA receptors in order to avoid any neuronal injury. <ref name="Structural Rearrangements of NR1/NR2A NMDA Receptors during Allosteric Inhibition">DOI 10.1016/j.neuron.2010.08.011</ref> This very important regulation can act at the level of NR2A subunit.
+A '''high quantity of stress''' can lead to the '''overactivation''' of NMDA receptors. Therefore, a regulation can occur on NMDA receptors in order to avoid any neuronal injury. <ref name="Structural Rearrangements of NR1/NR2A NMDA Receptors during Allosteric Inhibition">DOI 10.1016/j.neuron.2010.08.011</ref> This very important regulation can act at the level of NR2A subunit.
 For now, scientists know that regulation can occur in several ways: either a modification directly affects the functioning of the receptor, or the quantity of receptors at the surface of the neuron by modifying NR2A itself or not.
@@ Line 58: / Line 58: @@
 '''•	Inhibition by Zn2+ '''
-Zn2+ exercises a control on the functioning of NR2A.  Zn2+ is considered to be an endogenous inhibitor of NMDA receptors. Indeed, the NTD of NR2A subunit forms a binding site for Zn2+.
+Zn2+ exercises a control on the functioning of NR2A.  Zn2+ is considered to be an '''endogenous inhibitor''' of NMDA receptors. Indeed, the NTD of NR2A subunit forms a binding site for Zn2+.
 The binding of Zn2+ on NR2A generates an allosteric modulation of NMDA receptor, leading to its closure. The molecular mechanisms by which the NTD can communicate the inhibitory change of conformation to the rest of the receptor is still unknown. Nevertheless, the LBD was identified as a major intermediate between the NTD to the channel gate.
@@ Line 71: / Line 71: @@
 '''•	Inhibition by palmitoylation directly on NR2A'''
-NR2A has two distinct consensus cysteine clusters in its C-terminal region, which are susceptible to be [https://en.wikipedia.org/wiki/Palmitoylation palmitoylated].
+NR2A has '''two distinct consensus cysteine clusters''' in its C-terminal region, which are susceptible to be [https://en.wikipedia.org/wiki/Palmitoylation palmitoylated].
 If the first cluster is palmitoylated, the activity of some tyrosine kinases is increased. Their phosphorylations lead to enhanced stability of NMDA receptors on the cell surface, but also ensure their proper surface delivery from the Golgi apparatus. In contrast, depalmitoylation of this cluster decreases the surface NMDA receptors, because there are less stably associated with the plasma membrane.