6y95

From Proteopedia

(Difference between revisions)

Revision as of 11:08, 14 June 2023

Ca2+-free Calmodulin mutant N53I

Structural highlights

6y95 is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Mutations in the genes encoding the highly conserved Ca(2+)-sensing protein calmodulin (CaM) cause severe cardiac arrhythmias, including catecholaminergic polymorphic ventricular tachycardia (CPVT) or long QT syndrome, and sudden cardiac death. Most of the identified arrhythmogenic mutations reside in the C-terminal domain of CaM, and mostly affect Ca(2+)-coordinating residues. One exception is the CPVT-causing N53I substitution, which resides in the N-terminal domain (N-domain). It does not affect Ca(2+)-coordination and has only a minor impact on binding affinity toward Ca(2+) and on other biophysical properties. Nevertheless, the N53I substitution dramatically affects CaM's ability to reduce the open probability of the cardiac ryanodine receptor (RyR2), while having no effect on the regulation of the plasmalemmal voltage-gated Ca(2+) channel, Cav1.2. To gain more insights into the molecular disease mechanism of this mutant, we used NMR to investigate the structures and dynamics of both apo- and Ca(2+)-bound CaM-N53I in solution. We also solved the crystal structures of wild-type and N53I CaM in complex with the primary calmodulin binding domain (CaMBD2) from RyR2 at 1.84-2.13 A resolutions. We found that all structures of the arrhythmogenic CaM-N53I variant are highly similar to those of wild type CaM. However, we noted that the N53I substitution exposes an additional hydrophobic surface, and that the intramolecular dynamics of the protein are significantly altered such that they destabilize the CaM N-domain. We conclude that the N53I-induced changes alter the interaction of the CaM N-domain with RyR2 and thereby likely cause the arrhythmogenic phenotype of this mutation.

The arrhythmogenic N53I variant subtly changes the structure and dynamics in the calmodulin N-domain, altering its interaction with the cardiac ryanodine receptor.,Holt C, Hamborg L, Lau K, Brohus M, Sorensen AB, Larsen KT, Sommer C, Van Petegem F, Overgaard MT, Wimmer R J Biol Chem. 2020 Apr 21. pii: RA120.013430. doi: 10.1074/jbc.RA120.013430. PMID:32317284^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Holt C, Hamborg L, Lau K, Brohus M, Sorensen AB, Larsen KT, Sommer C, Van Petegem F, Overgaard MT, Wimmer R. The arrhythmogenic N53I variant subtly changes the structure and dynamics in the calmodulin N-domain, altering its interaction with the cardiac ryanodine receptor. J Biol Chem. 2020 Apr 21. pii: RA120.013430. doi: 10.1074/jbc.RA120.013430. PMID:32317284 doi:http://dx.doi.org/10.1074/jbc.RA120.013430

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 See Also
6 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6y95"

@@ Line 1: / Line 1: @@
 ==Ca2+-free Calmodulin mutant N53I==
-<StructureSection load='6y95' size='340' side='right'caption='[[6y95]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>
+<StructureSection load='6y95' size='340' side='right'caption='[[6y95]]' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6y95]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y95 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y95 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6y95]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y95 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Y95 FirstGlance]. <br>
-</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CALM1, CALM, CAM, CAM1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+</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=6y95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y95 OCA], [https://pdbe.org/6y95 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6y95 RCSB], [https://www.ebi.ac.uk/pdbsum/6y95 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6y95 ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6y95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y95 OCA], [http://pdbe.org/6y95 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y95 RCSB], [http://www.ebi.ac.uk/pdbsum/6y95 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y95 ProSAT]</span></td></tr>
 </table>
 == 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.
+[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 ==
-[[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>
+[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 ==
@@ Line 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 6y95" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Calmodulin 3D structures|Calmodulin 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Brohus, M]]
+[[Category: Brohus M]]
-[[Category: Hamborg, L N]]
+[[Category: Hamborg LN]]
-[[Category: Holt, C]]
+[[Category: Holt C]]
-[[Category: Larsen, K T]]
+[[Category: Larsen KT]]
-[[Category: Lau, K]]
+[[Category: Lau K]]
-[[Category: Overgaard, M T]]
+[[Category: Overgaard MT]]
-[[Category: Petegem, F V]]
+[[Category: Petegem FV]]
-[[Category: Sommer, C]]
+[[Category: Sommer C]]
-[[Category: Sorensen, A B]]
+[[Category: Sorensen AB]]
-[[Category: Wimmer, R]]
+[[Category: Wimmer R]]
-[[Category: Cpvt]]
-[[Category: Metal binding protein]]
-[[Category: Metal-binding]]
-[[Category: Mutant]]
-[[Category: Signaling protein]]

6y95

From Proteopedia

Revision as of 11:08, 14 June 2023

Ca2+-free Calmodulin mutant N53I

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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