Sandbox Reserved 1649: Difference between revisions
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== NR2A (2A5S) == | == NR2A (2A5S) == | ||
NR2A is a protein which is a part of [https://en.wikipedia.org/wiki/NMDA_receptor NMDA receptors], heterodimer channels composed of four subunits. Indeed, NMDA receptors are made of the association between two NR2 and two NR1 proteins. NMDA receptors play a key role in mammalian central nervous system, as they act in Ca2+ influx in synapses in response to glutamate and glycine binding. Their role is essential for learning and memory. Variety of NR2 allows modulation of NMDAr. In the other hand, [https://www.youtube.com/watch?fbclid=IwAR163EHEh3RM8BXt-_4aiecrCgkF83HoyOefyU63d_CQwoqN5RHShYfLDnM&v=4-DuvwoH2zQ&feat NMDA | NR2A is a protein which is a part of [https://en.wikipedia.org/wiki/NMDA_receptor NMDA receptors], that are heterodimer channels composed of four subunits. Indeed, NMDA receptors are made of the association between two NR2 and two NR1 proteins. NMDA receptors play a key role in mammalian central nervous system, as they act in Ca2+ influx in synapses in response to glutamate and glycine binding. Their role is essential for learning and memory. Variety of NR2 allows modulation of NMDAr. In the other hand, [https://www.youtube.com/watch?fbclid=IwAR163EHEh3RM8BXt-_4aiecrCgkF83HoyOefyU63d_CQwoqN5RHShYfLDnM&v=4-DuvwoH2zQ&feat NMDA receptors are related to AMPA receptors in the same synapse.] | ||
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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 | 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)''' | '''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 | 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 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 salt bridge with agonist. In NR2A D731 (which corresponds to <scene name='86/868182/D213/3'>D213</scene>) is not able to do salt bridge with amino group because 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). | 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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'''CTD''' | '''CTD''' | ||
CTD domain is the less conserved of NR2 | 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 == | == Regulation == | ||
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NR1 and NR2A are assembled in a dimer ([[https://proteopedia.org/wiki/index.php/2a5t?fbclid=IwAR0lozEgKTJwNjr16Sklgz0epz2LLAsw769SkhGuuuNIV3ZaEz2dY2EPNxk Complex NR1/NR2a]]), arranged in a back-to-back fashion, thanks to interactions between three different domains on each subunit: sites I, II and III. | NR1 and NR2A are assembled in a dimer ([[https://proteopedia.org/wiki/index.php/2a5t?fbclid=IwAR0lozEgKTJwNjr16Sklgz0epz2LLAsw769SkhGuuuNIV3ZaEz2dY2EPNxk Complex NR1/NR2a]]), arranged in a back-to-back fashion, thanks to interactions between three different domains on each subunit: sites I, II and III. | ||
- Site II: The link between NR2A and NR1 is made by at least three amino acids: E530 (<scene name='86/868182/E68/2'>E68 in LBD</scene>) makes a salt bridge with R755 of NR1, F524 (<scene name='86/868182/F62/2'>F62 in LBD</scene>) binds K531 of NR1 by a hydrogen bond on the backbone carbonyl oxygen, and P257. | - Site II: The link between NR2A and NR1 is made by at least three amino acids: E530 (<scene name='86/868182/E68/2'>E68 in LBD</scene>) makes a salt bridge with R755 of NR1, F524 (<scene name='86/868182/F62/2'>F62 in LBD</scene>) binds K531 of NR1 by a hydrogen bond on the backbone carbonyl oxygen, and P257. | ||
- Sites I and III: the binding is established by hydrophobic residues (I514 (<scene name='86/868182/I52/2'>I52 in LBD</scene>), V526 (<scene name='86/868182/V64/2'>V64 in LBD</scene>), L777, L780 present on helices D and J), or by polar contacts | - Sites I and III: the binding is established by hydrophobic residues (I514 (<scene name='86/868182/I52/2'>I52 in LBD</scene>), V526 (<scene name='86/868182/V64/2'>V64 in LBD</scene>), L777, L780 present on helices D and J), or by polar contacts | ||
