6y94

<StructureSection load='6y94' size='340' side='right'caption='[[6y94]], [[NMR_Ensembles_of_Models | 20 NMR models]]' scene=''>

<table><tr><td colspan='2'>[[6y94]] 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=6Y94 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Y94 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">CALM1, CALM, CAM, CAM1 ([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'>[http://proteopedia.org/fgij/fg.htm?mol=6y94 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6y94 OCA], [http://pdbe.org/6y94 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6y94 RCSB], [http://www.ebi.ac.uk/pdbsum/6y94 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6y94 ProSAT]</span></td></tr>

== 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.

== 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>

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== 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.

 

== References ==

[[Category: Human]]

[[Category: Brohus, M]]

[[Category: Holt, C]]

[[Category: Larsen, K T]]

[[Category: Lau, K]]

[[Category: Nielsen, L H]]

[[Category: Overgaard, M T]]

[[Category: Petegem, F V]]

[[Category: Sommer, C]]

[[Category: Sorensen, A B]]

[[Category: Wimmer, R]]

[[Category: Signaling protein]]