|
|
| (2 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| | | | |
| | ==1.65 Angstrom crystal structure of the N97I Ca/CaM:CaV1.2 IQ domain complex== | | ==1.65 Angstrom crystal structure of the N97I Ca/CaM:CaV1.2 IQ domain complex== |
| - | <StructureSection load='6dad' size='340' side='right' caption='[[6dad]], [[Resolution|resolution]] 1.65Å' scene=''> | + | <StructureSection load='6dad' size='340' side='right'caption='[[6dad]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6dad]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DAD OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DAD FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6dad]] is a 4 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=6DAD OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DAD 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></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.65Å</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=6dad FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dad OCA], [http://pdbe.org/6dad PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dad RCSB], [http://www.ebi.ac.uk/pdbsum/6dad PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dad ProSAT]</span></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></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=6dad FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dad OCA], [https://pdbe.org/6dad PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dad RCSB], [https://www.ebi.ac.uk/pdbsum/6dad PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dad ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://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. [[http://www.uniprot.org/uniprot/CAC1C_HUMAN CAC1C_HUMAN]] Defects in CACNA1C are the cause of Timothy syndrome (TS) [MIM:[http://omim.org/entry/601005 601005]]. TS is a disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities and autism.<ref>PMID:15454078</ref> <ref>PMID:15863612</ref> Defects in CACNA1C are the cause of Brugada syndrome type 3 (BRGDA3) [MIM:[http://omim.org/entry/611875 611875]]. A heart disease characterized by the association of Brugada syndrome with shortened QT intervals. Brugada syndrome is a 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:17224476</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/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> [[http://www.uniprot.org/uniprot/CAC1C_HUMAN CAC1C_HUMAN]] Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1C gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin-GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1C subunit play an important role in excitation-contraction coupling in the heart. The various isoforms display marked differences in the sensitivity to DHP compounds. Binding of calmodulin or CABP1 at the same regulatory sites results in an opposit effects on the channel function.<ref>PMID:8392192</ref> <ref>PMID:7737988</ref> <ref>PMID:9013606</ref> <ref>PMID:9607315</ref> <ref>PMID:12176756</ref> <ref>PMID:17071743</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;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Calmodulin (CaM) represents one of the most conserved proteins among eukaryotes and is known to bind and modulate more than a 100 targets. Recently, several disease-associated mutations have been identified in the CALM genes that are causative of severe cardiac arrhythmia syndromes. Although several mutations have been shown to affect the function of various cardiac ion channels, direct structural insights into any CaM disease mutation have been lacking. Here we report a crystallographic and NMR investigation of several disease mutant CaMs, linked to long-QT syndrome, in complex with the IQ domain of the cardiac voltage-gated calcium channel (CaV1.2). Surprisingly, two mutants (D95V, N97I) cause a major distortion of the C-terminal lobe, resulting in a pathological conformation not reported before. These structural changes result in altered interactions with the CaV1.2 IQ domain. Another mutation (N97S) reduces the affinity for Ca(2+) by introducing strain in EF hand 3. A fourth mutant (F141L) shows structural changes in the Ca(2+)-free state that increase the affinity for the IQ domain. These results thus show that different mechanisms underlie the ability of CaM disease mutations to affect Ca(2+)-dependent inactivation of the voltage-gated calcium channel. |
| | + | |
| | + | Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel.,Wang K, Holt C, Lu J, Brohus M, Larsen KT, Overgaard MT, Wimmer R, Van Petegem F Proc Natl Acad Sci U S A. 2018 Oct 22. pii: 1808733115. doi:, 10.1073/pnas.1808733115. PMID:30348784<ref>PMID:30348784</ref> |
| | + | |
| | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | + | </div> |
| | + | <div class="pdbe-citations 6dad" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Calmodulin 3D structures|Calmodulin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Petegem, F Van]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Wang, K]] | + | [[Category: Large Structures]] |
| - | [[Category: Calcium binding protein-membrane protein complex]] | + | [[Category: Van Petegem F]] |
| - | [[Category: Calmodulin]] | + | [[Category: Wang K]] |
| - | [[Category: Complex]]
| + | |
| - | [[Category: Mutant]]
| + | |
| 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
Calmodulin (CaM) represents one of the most conserved proteins among eukaryotes and is known to bind and modulate more than a 100 targets. Recently, several disease-associated mutations have been identified in the CALM genes that are causative of severe cardiac arrhythmia syndromes. Although several mutations have been shown to affect the function of various cardiac ion channels, direct structural insights into any CaM disease mutation have been lacking. Here we report a crystallographic and NMR investigation of several disease mutant CaMs, linked to long-QT syndrome, in complex with the IQ domain of the cardiac voltage-gated calcium channel (CaV1.2). Surprisingly, two mutants (D95V, N97I) cause a major distortion of the C-terminal lobe, resulting in a pathological conformation not reported before. These structural changes result in altered interactions with the CaV1.2 IQ domain. Another mutation (N97S) reduces the affinity for Ca(2+) by introducing strain in EF hand 3. A fourth mutant (F141L) shows structural changes in the Ca(2+)-free state that increase the affinity for the IQ domain. These results thus show that different mechanisms underlie the ability of CaM disease mutations to affect Ca(2+)-dependent inactivation of the voltage-gated calcium channel.
Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel.,Wang K, Holt C, Lu J, Brohus M, Larsen KT, Overgaard MT, Wimmer R, Van Petegem F Proc Natl Acad Sci U S A. 2018 Oct 22. pii: 1808733115. doi:, 10.1073/pnas.1808733115. PMID:30348784[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
- ↑ Wang K, Holt C, Lu J, Brohus M, Larsen KT, Overgaard MT, Wimmer R, Van Petegem F. Arrhythmia mutations in calmodulin cause conformational changes that affect interactions with the cardiac voltage-gated calcium channel. Proc Natl Acad Sci U S A. 2018 Oct 22. pii: 1808733115. doi:, 10.1073/pnas.1808733115. PMID:30348784 doi:http://dx.doi.org/10.1073/pnas.1808733115
|
