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NMR Structure of Ca2+/Calmodulin bound to the GluN1 C0 domain of the NMDA receptor
Structural highlights
DiseaseCALM1_HUMAN The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of CPVT4. The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM1 are the cause of LQT14. FunctionCALM1_HUMAN Calmodulin mediates the control of a large number of enzymes, ion channels, aquaporins and other proteins through calcium-binding. Among the enzymes to be stimulated by the calmodulin-calcium complex are a number of protein kinases and phosphatases. Together with CCP110 and centrin, is involved in a genetic pathway that regulates the centrosome cycle and progression through cytokinesis (PubMed:16760425). Mediates calcium-dependent inactivation of CACNA1C (PubMed:26969752). Positively regulates calcium-activated potassium channel activity of KCNN2 (PubMed:27165696).[1] [2] [3] [4] Publication Abstract from PubMedThe synaptic plasticity mechanisms that are thought to underlie learning and memory require Ca(2+) influx mediated by N-methyl-D-aspartate receptors composed of glycine-binding GluN1 and glutamate-binding GluN2 subunits. Calmodulin (CaM) binding to the cytosolic regions in both GluN1 (residues 841-865, called GluN1-C0) and GluN2A (residues 1004-1023, called GluN2A-C0) may be important for Ca(2+)-dependent channel desensitization (CDD). Here, we report NMR, ITC and electrophysiological experiments to probe the structure and functional role of Ca(2+)-bound CaM (Ca(2+)-CaM) binding to both GluN1 and GluN2A subunits. Our ITC studies show that the GluN1-C0 peptide binds to both the N-lobe and C-lobe of Ca(2+)-CaM, whereas the GluN2A-C0 peptide binds to only the Ca(2+)-CaM C-lobe. Our NMR analysis reveals GluN2A residues (W1014 and V1018) interact with exposed hydrophobic residues in the Ca(2+)-CaM C-lobe. The NMR structure of Ca(2+)-CaM bound to the GluN1-C0 peptide indicates the two CaM lobes bind to opposite sides of the GluN1-C0 helix (C-lobe contacts M848, F852, A853 and N-lobe contacts A854, V855, W858). The GluN1 mutant F852E and the GluN2A mutant W1014E both perturbed CaM binding in ITC studies, and also diminished electrophysiologically-measured CDD, suggesting CaM interaction with these residues contributes to CDD. We propose a structural mechanism of CDD wherein channel desensitization is caused by the binding of four CaM per N-methyl-D-aspartate receptor subunit tetramer. Structural basis and functional analysis of NMDA receptor regulation by calmodulin.,Bej A, Erickson-Oberg MQ, Nigam A, Yu I, Hell JW, Johnson JW, Ames JB J Biol Chem. 2026 Jan 7;302(2):111131. doi: 10.1016/j.jbc.2026.111131. PMID:41513089[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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