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6y4o

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Revision as of 11:39, 29 July 2020

Calmodulin bound to cardiac ryanodine receptor (RyR2) calmodulin binding domain

Structural highlights

6y4o is a 2 chain structure with sequence from African bush elephant and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	CALM2, CAM2, CAMB (HUMAN), Ryr2 (African bush elephant)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CALM2_HUMAN] Catecholaminergic polymorphic ventricular tachycardia;Brugada syndrome;Romano-Ward syndrome. The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM2 are the cause of LQT15.

Function

[CALM2_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] [RYR2_MOUSE] Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering cardiac muscle contraction. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development.^[4] ^[5] ^[6] ^[7]

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^[8]

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
↑ 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
↑ Zhao M, Li P, Li X, Zhang L, Winkfein RJ, Chen SR. Molecular identification of the ryanodine receptor pore-forming segment. J Biol Chem. 1999 Sep 10;274(37):25971-4. PMID:10473538
↑ Takeshima H, Komazaki S, Hirose K, Nishi M, Noda T, Iino M. Embryonic lethality and abnormal cardiac myocytes in mice lacking ryanodine receptor type 2. EMBO J. 1998 Jun 15;17(12):3309-16. PMID:9628868 doi:10.1093/emboj/17.12.3309
↑ van Oort RJ, McCauley MD, Dixit SS, Pereira L, Yang Y, Respress JL, Wang Q, De Almeida AC, Skapura DG, Anderson ME, Bers DM, Wehrens XH. Ryanodine receptor phosphorylation by calcium/calmodulin-dependent protein kinase II promotes life-threatening ventricular arrhythmias in mice with heart failure. Circulation. 2010 Dec 21;122(25):2669-79. doi: 10.1161/CIRCULATIONAHA.110.982298., Epub 2010 Nov 15. PMID:21098440 doi:10.1161/CIRCULATIONAHA.110.982298
↑ Guo T, Cornea RL, Huke S, Camors E, Yang Y, Picht E, Fruen BR, Bers DM. Kinetics of FKBP12.6 binding to ryanodine receptors in permeabilized cardiac myocytes and effects on Ca sparks. Circ Res. 2010 Jun 11;106(11):1743-52. doi: 10.1161/CIRCRESAHA.110.219816. Epub, 2010 Apr 29. PMID:20431056 doi:10.1161/CIRCRESAHA.110.219816
↑ 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 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6y4o"

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[6y4o]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/African_bush_elephant African bush elephant] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Y4O OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y4O 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></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CALM2, CAM2, CAMB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), RYR3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9785 African bush elephant])</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CALM2, CAM2, CAMB ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), Ryr2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9785 African bush elephant])</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=6y4o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y4o OCA], [http://pdbe.org/6y4o PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y4o RCSB], [http://www.ebi.ac.uk/pdbsum/6y4o PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y4o ProSAT]</span></td></tr>
 </table>
@@ Line 11: / Line 11: @@
 [[http://www.uniprot.org/uniprot/CALM2_HUMAN CALM2_HUMAN]] Catecholaminergic polymorphic ventricular tachycardia;Brugada syndrome;Romano-Ward syndrome. The disease is caused by mutations affecting the gene represented in this entry. Mutations in CALM2 are the cause of LQT15.
 == Function ==
-[[http://www.uniprot.org/uniprot/CALM2_HUMAN CALM2_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:26969752</ref> <ref>PMID:27165696</ref>
+[[http://www.uniprot.org/uniprot/CALM2_HUMAN CALM2_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:26969752</ref> <ref>PMID:27165696</ref>  [[http://www.uniprot.org/uniprot/RYR2_MOUSE RYR2_MOUSE]] Calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm and thereby plays a key role in triggering cardiac muscle contraction. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development.<ref>PMID:10473538</ref> <ref>PMID:9628868</ref> <ref>PMID:21098440</ref> <ref>PMID:20431056</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==

6y4o

From Proteopedia

Revision as of 11:39, 29 July 2020

Calmodulin bound to cardiac ryanodine receptor (RyR2) calmodulin binding domain

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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