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| | ==1.35 A crystal structure of the NaV1.5 DIII-IV-Ca/CaM complex== | | ==1.35 A crystal structure of the NaV1.5 DIII-IV-Ca/CaM complex== |
| - | <StructureSection load='4djc' size='340' side='right' caption='[[4djc]], [[Resolution|resolution]] 1.35Å' scene=''> | + | <StructureSection load='4djc' size='340' side='right'caption='[[4djc]], [[Resolution|resolution]] 1.35Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4djc]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DJC OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DJC FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4djc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DJC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DJC FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=IPA:ISOPROPYL+ALCOHOL'>IPA</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CALM1, CALM, CAM, CAM1, CALM2, CAM2, CAMB, CALM3, CALML2, CAM3, CAMC, CAMIII ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), SCN5A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4djc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4djc OCA], [https://pdbe.org/4djc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4djc RCSB], [https://www.ebi.ac.uk/pdbsum/4djc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4djc ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4djc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4djc OCA], [http://pdbe.org/4djc PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4djc RCSB], [http://www.ebi.ac.uk/pdbsum/4djc PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4djc ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/SCN5A_HUMAN SCN5A_HUMAN]] Defects in SCN5A are a cause of progressive familial heart block type 1A (PFHB1A) [MIM:[http://omim.org/entry/113900 113900]]; also known as Lenegre-Lev disease or progressive cardiac conduction defect (PCCD). PFHB1A is an autosomal dominant cardiac bundle branch disorder that may progress to complete heart block. PFHB1A is characterized by progressive alteration of cardiac conduction through the His-Purkinje system with right or left bundle branch block and widening of QRS complexes, leading to complete atrioventricular block and causing syncope and sudden death.<ref>PMID:10471492</ref> <ref>PMID:11234013</ref> <ref>PMID:11804990</ref> <ref>PMID:12574143</ref> <ref>PMID:12569159</ref> <ref>PMID:19251209</ref> Defects in SCN5A are the cause of long QT syndrome type 3 (LQT3) [MIM:[http://omim.org/entry/603830 603830]]. Long QT syndromes are heart disorders characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress. LQT3 inheritance is an autosomal dominant.<ref>PMID:10471492</ref> <ref>PMID:12454206</ref> <ref>PMID:7889574</ref> <ref>PMID:8541846</ref> <ref>PMID:7651517</ref> <ref>PMID:9686753</ref> <ref>PMID:9506831</ref> <ref>PMID:10627139</ref> [:]<ref>PMID:10508990</ref> <ref>PMID:10377081</ref> <ref>PMID:10590249</ref> <ref>PMID:10973849</ref> <ref>PMID:10911008</ref> <ref>PMID:11304498</ref> <ref>PMID:11410597</ref> <ref>PMID:11710892</ref> <ref>PMID:11889015</ref> <ref>PMID:11997281</ref> <ref>PMID:12209021</ref> <ref>PMID:12673799</ref> <ref>PMID:15840476</ref> <ref>PMID:16922724</ref> <ref>PMID:18708744</ref> <ref>PMID:18060054</ref> <ref>PMID:18929331</ref> <ref>PMID:18848812</ref> <ref>PMID:18451998</ref> <ref>PMID:21109022</ref> Defects in SCN5A are the cause of Brugada syndrome type 1 (BRGDA1) [MIM:[http://omim.org/entry/601144 601144]]. An autosomal dominant tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs (called ventricular fibrillation), the individual will faint and may die in a few minutes if the heart is not reset.<ref>PMID:10471492</ref> <ref>PMID:19251209</ref> <ref>PMID:11410597</ref> <ref>PMID:9521325</ref> <ref>PMID:10690282</ref> <ref>PMID:10532948</ref> <ref>PMID:10618304</ref> <ref>PMID:12106943</ref> <ref>PMID:11901046</ref> <ref>PMID:11823453</ref> <ref>PMID:12051963</ref> <ref>PMID:15023552</ref> <ref>PMID:15338453</ref> <ref>PMID:15579534</ref> <ref>PMID:16266370</ref> <ref>PMID:15851320</ref> <ref>PMID:16325048</ref> <ref>PMID:16616735</ref> <ref>PMID:17075016</ref> <ref>PMID:17081365</ref> <ref>PMID:17198989</ref> <ref>PMID:18341814</ref> <ref>PMID:18616619</ref> <ref>PMID:18456723</ref> <ref>PMID:18252757</ref> <ref>PMID:19272188</ref> Defects in SCN5A are the cause of sick sinus syndrome type 1 (SSS1) [MIM:[http://omim.org/entry/608567 608567]]. The term 'sick sinus syndrome' encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia ('tachycardia-bradycardia syndrome') are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors, in which case it is considered to be a congenital disorder.<ref>PMID:10471492</ref> <ref>PMID:11748104</ref> <ref>PMID:14523039</ref> <ref>PMID:22795782</ref> Defects in SCN5A are the cause of familial paroxysmal ventricular fibrillation type 1 (VF1) [MIM:[http://omim.org/entry/603829 603829]]. A cardiac arrhythmia marked by fibrillary contractions of the ventricular muscle due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the ventricle and by absence of atrial activity.<ref>PMID:10471492</ref> <ref>PMID:10940383</ref> Defects in SCN5A may be a cause of sudden infant death syndrome (SIDS) [MIM:[http://omim.org/entry/272120 272120]]. SIDS is the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of clinical history. Pathophysiologic mechanisms for SIDS may include respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, but definitive pathogenic mechanisms precipitating an infant sudden death remain elusive. Long QT syndromes-associated mutations can be responsible for some of SIDS cases.<ref>PMID:10471492</ref> <ref>PMID:18596570</ref> <ref>PMID:19302788</ref> Defects in SCN5A may be a cause of familial atrial standstill (FAS) [MIM:[http://omim.org/entry/108770 108770]]. Atrial standstill is an extremely rare arrhythmia, characterized by the absence of electrical and mechanical activity in the atria. Electrocardiographically, it is characterized by bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm.<ref>PMID:10471492</ref> <ref>PMID:12522116</ref> Defects in SCN5A are the cause of cardiomyopathy dilated type 1E (CMD1E) [MIM:[http://omim.org/entry/601154 601154]]; also known as dilated cardiomyopathy with conduction disorder and arrhythmia or dilated cardiomyopathy with conduction defect 2. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.<ref>PMID:10471492</ref> <ref>PMID:15466643</ref> Defects in SCN5A are the cause of familial atrial fibrillation type 10 (ATFB10) [MIM:[http://omim.org/entry/614022 614022]]. ATFB10 is a familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure.<ref>PMID:10471492</ref> <ref>PMID:18378609</ref> <ref>PMID:18088563</ref> | + | [[https://www.uniprot.org/uniprot/CALM1_HUMAN 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 == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/SCN5A_HUMAN SCN5A_HUMAN]] This protein mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient. It is a tetrodotoxin-resistant Na(+) channel isoform. This channel is responsible for the initial upstroke of the action potential. Channel inactivation is regulated by intracellular calcium levels.<ref>PMID:19074138</ref> | + | [[https://www.uniprot.org/uniprot/CALM1_HUMAN 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).<ref>PMID:16760425</ref> <ref>PMID:23893133</ref> <ref>PMID:26969752</ref> <ref>PMID:27165696</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Calmodulin|Calmodulin]] | + | *[[Calmodulin 3D structures|Calmodulin 3D structures]] |
| | + | *[[Ion channels 3D structures|Ion channels 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Ahern, C A]] | + | [[Category: Large Structures]] |
| - | [[Category: Petegem, FVan]] | + | [[Category: Ahern CA]] |
| - | [[Category: Sarhan, M F]] | + | [[Category: Sarhan MF]] |
| - | [[Category: Tung, C C]] | + | [[Category: Tung C-C]] |
| - | [[Category: Calcium-binding protein]] | + | [[Category: Van Petegem F]] |
| - | [[Category: Ef-hand]]
| + | |
| 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 PubMed
Voltage-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.
See Also
References
- ↑ Tsang WY, Spektor A, Luciano DJ, Indjeian VB, Chen Z, Salisbury JL, Sanchez I, Dynlacht BD. CP110 cooperates with two calcium-binding proteins to regulate cytokinesis and genome stability. Mol Biol Cell. 2006 Aug;17(8):3423-34. Epub 2006 Jun 7. PMID:16760425 doi:10.1091/mbc.E06-04-0371
- ↑ Reichow SL, Clemens DM, Freites JA, Nemeth-Cahalan KL, Heyden M, Tobias DJ, Hall JE, Gonen T. Allosteric mechanism of water-channel gating by Ca-calmodulin. Nat Struct Mol Biol. 2013 Jul 28. doi: 10.1038/nsmb.2630. PMID:23893133 doi:10.1038/nsmb.2630
- ↑ Boczek NJ, Gomez-Hurtado N, Ye D, Calvert ML, Tester DJ, Kryshtal D, Hwang HS, Johnson CN, Chazin WJ, Loporcaro CG, Shah M, Papez AL, Lau YR, Kanter R, Knollmann BC, Ackerman MJ. Spectrum and Prevalence of CALM1-, CALM2-, and CALM3-Encoded Calmodulin Variants in Long QT Syndrome and Functional Characterization of a Novel Long QT Syndrome-Associated Calmodulin Missense Variant, E141G. Circ Cardiovasc Genet. 2016 Apr;9(2):136-146. doi:, 10.1161/CIRCGENETICS.115.001323. Epub 2016 Mar 11. PMID:26969752 doi:http://dx.doi.org/10.1161/CIRCGENETICS.115.001323
- ↑ Yu CC, Ko JS, Ai T, Tsai WC, Chen Z, Rubart M, Vatta M, Everett TH 4th, George AL Jr, Chen PS. Arrhythmogenic calmodulin mutations impede activation of small-conductance calcium-activated potassium current. Heart Rhythm. 2016 Aug;13(8):1716-23. doi: 10.1016/j.hrthm.2016.05.009. Epub 2016, May 7. PMID:27165696 doi:http://dx.doi.org/10.1016/j.hrthm.2016.05.009
- ↑ Sarhan MF, Tung CC, Van Petegem F, Ahern CA. Crystallographic basis for calcium regulation of sodium channels. Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3558-63. Epub 2012 Feb 13. PMID:22331908 doi:10.1073/pnas.1114748109
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