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| | <StructureSection load='2vay' size='340' side='right'caption='[[2vay]], [[Resolution|resolution]] 1.94Å' scene=''> | | <StructureSection load='2vay' size='340' side='right'caption='[[2vay]], [[Resolution|resolution]] 1.94Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2vay]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VAY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VAY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2vay]] 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=2VAY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VAY FirstGlance]. <br> |
| - | </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=CL:CHLORIDE+ION'>CL</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]] 1.94Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1aji|1aji]], [[1cdl|1cdl]], [[1cll|1cll]], [[1iwq|1iwq]], [[1j7o|1j7o]], [[1j7p|1j7p]], [[1l7z|1l7z]], [[1pk0|1pk0]], [[1s26|1s26]], [[1sw8|1sw8]], [[1xfu|1xfu]], [[1xfv|1xfv]], [[1xfw|1xfw]], [[1xfy|1xfy]], [[1yr5|1yr5]], [[1yru|1yru]], [[1zot|1zot]], [[2v01|2v01]], [[2v02|2v02]], [[1ctr|1ctr]], [[1k90|1k90]], [[1k93|1k93]], [[1lvc|1lvc]], [[1nkf|1nkf]], [[1sk6|1sk6]], [[1wrz|1wrz]], [[1xfx|1xfx]], [[1xfz|1xfz]], [[1y6w|1y6w]], [[1yrt|1yrt]], [[2be6|2be6]], [[2f3y|2f3y]], [[2f3z|2f3z]]</div></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=CL:CHLORIDE+ION'>CL</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=2vay FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vay OCA], [https://pdbe.org/2vay PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vay RCSB], [https://www.ebi.ac.uk/pdbsum/2vay PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vay ProSAT]</span></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=2vay FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vay OCA], [https://pdbe.org/2vay PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vay RCSB], [https://www.ebi.ac.uk/pdbsum/2vay PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vay ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[https://www.uniprot.org/uniprot/CAC1S_HUMAN CAC1S_HUMAN]] Defects in CACNA1S are the cause of periodic paralysis hypokalemic type 1 (HOKPP1) [MIM:[https://omim.org/entry/170400 170400]]; also designated HYPOPP. HOKPP1 is an autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels.<ref>PMID:8004673</ref> <ref>PMID:7987325</ref> <ref>PMID:18162704</ref> <ref>PMID:17418573</ref> <ref>PMID:19118277</ref> Genetic variations in CACNA1S are the cause of susceptibility to malignant hyperthermia 5 (MHS5) [MIM:[https://omim.org/entry/601887 601887]]; an autosomal dominant disorder that is potentially lethal in susceptible individuals on exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants.<ref>PMID:9199552</ref> Defects in CACNA1S are the cause of susceptibility to thyrotoxic periodic paralysis type 1 (TTPP1) [MIM:[https://omim.org/entry/188580 188580]]. A sporadic muscular disorder characterized by episodic weakness and hypokalemia during a thyrotoxic state. It is clinically similar to hereditary hypokalemic periodic paralysis, except for the fact that hyperthyroidism is an absolute requirement for disease manifestation. The disease presents with recurrent episodes of acute muscular weakness of the four extremities that vary in severity from paresis to complete paralysis. Attacks are triggered by ingestion of a high carbohydrate load or strenuous physical activity followed by a period of rest. Thyrotoxic periodic paralysis can occur in association with any cause of hyperthyroidism, but is most commonly associated with Graves disease.<ref>PMID:15001631</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 == |
| - | [[https://www.uniprot.org/uniprot/CAC1S_HUMAN CAC1S_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-1S 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-1S subunit play an important role in excitation-contraction coupling in skeletal muscle.
| + | [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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Black, D J]] | + | [[Category: Black DJ]] |
| - | [[Category: Halling, D B]] | + | [[Category: Halling DB]] |
| - | [[Category: Hamilton, S L]] | + | [[Category: Hamilton SL]] |
| - | [[Category: Pedersen, S E]] | + | [[Category: Pedersen SE]] |
| - | [[Category: Acetylation]]
| + | |
| - | [[Category: Alpha-1s subunit]]
| + | |
| - | [[Category: Calcium]]
| + | |
| - | [[Category: Calcium channel]]
| + | |
| - | [[Category: Calcium transport]]
| + | |
| - | [[Category: Cav]]
| + | |
| - | [[Category: Dihydropyridine receptor]]
| + | |
| - | [[Category: Excitation-contraction coupling]]
| + | |
| - | [[Category: Ion transport]]
| + | |
| - | [[Category: Ionic channel]]
| + | |
| - | [[Category: L-type calcium channel]]
| + | |
| - | [[Category: Metal transport]]
| + | |
| - | [[Category: Methylation]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Skeletal muscle]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| - | [[Category: Transport]]
| + | |
| - | [[Category: Ubl conjugation]]
| + | |
| - | [[Category: Voltage-dependent]]
| + | |
| - | [[Category: Voltage-gated channel]]
| + | |
| 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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Calmodulin binds to IQ motifs in the alpha(1) subunit of Ca(V)1.1 and Ca(V)1.2, but the affinities of calmodulin for the motif and for Ca(2+) are higher when bound to Ca(V)1.2 IQ. The Ca(V)1.1 IQ and Ca(V)1.2 IQ sequences differ by four amino acids. We determined the structure of calmodulin bound to Ca(V)1.1 IQ and compared it with that of calmodulin bound to Ca(V)1.2 IQ. Four methionines in Ca(2+)-calmodulin form a hydrophobic binding pocket for the peptide, but only one of the four nonconserved amino acids (His-1532 of Ca(V)1.1 and Tyr-1675 of Ca(V)1.2) contacts this calmodulin pocket. However, Tyr-1675 in Ca(V)1.2 contributes only modestly to the higher affinity of this peptide for calmodulin; the other three amino acids in Ca(V)1.2 contribute significantly to the difference in the Ca(2+) affinity of the bound calmodulin despite having no direct contact with calmodulin. Those residues appear to allow an interaction with calmodulin with one lobe Ca(2+)-bound and one lobe Ca(2+)-free. Our data also provide evidence for lobe-lobe interactions in calmodulin bound to Ca(V)1.2.
Determinants in CaV1 channels that regulate the Ca2+ sensitivity of bound calmodulin.,Halling DB, Georgiou DK, Black DJ, Yang G, Fallon JL, Quiocho FA, Pedersen SE, Hamilton SL J Biol Chem. 2009 Jul 24;284(30):20041-51. Epub 2009 May 27. PMID:19473981[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
- ↑ Halling DB, Georgiou DK, Black DJ, Yang G, Fallon JL, Quiocho FA, Pedersen SE, Hamilton SL. Determinants in CaV1 channels that regulate the Ca2+ sensitivity of bound calmodulin. J Biol Chem. 2009 Jul 24;284(30):20041-51. Epub 2009 May 27. PMID:19473981 doi:10.1074/jbc.M109.013326
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