4djc
From Proteopedia
1.35 A crystal structure of the NaV1.5 DIII-IV-Ca/CaM complex
Structural highlights
Disease[CALM1_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. Function[CALM1_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 PubMedVoltage-gated sodium channels underlie the rapid regenerative upstroke of action potentials and are modulated by cytoplasmic calcium ions through a poorly understood mechanism. We describe the 1.35 A crystal structure of Ca(2+)-bound calmodulin (Ca(2+)/CaM) in complex with the inactivation gate (DIII-IV linker) of the cardiac sodium channel (Na(V)1.5). The complex harbors the positions of five disease mutations involved with long Q-T type 3 and Brugada syndromes. In conjunction with isothermal titration calorimetry, we identify unique inactivation-gate mutations that enhance or diminish Ca(2+)/CaM binding, which, in turn, sensitize or abolish Ca(2+) regulation of full-length channels in electrophysiological experiments. Additional biochemical experiments support a model whereby a single Ca(2+)/CaM bridges the C-terminal IQ motif to the DIII-IV linker via individual N and C lobes, respectively. The data suggest that Ca(2+)/CaM destabilizes binding of the inactivation gate to its receptor, thus biasing inactivation toward more depolarized potentials. Crystallographic basis for calcium regulation of sodium channels.,Sarhan MF, Tung CC, Van Petegem F, Ahern CA Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3558-63. Epub 2012 Feb 13. PMID:22331908[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. Loading citation details.. Citations No citations found See AlsoReferences
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