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Oxidative Susceptibility and Degradation of Calmodulin Cardiac Mutants
Author(s) -
Moen Rebecca Jane,
Julian Jordan,
Isehak Imad,
Thomas David Dale
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.04654
Subject(s) - catecholaminergic polymorphic ventricular tachycardia , ryanodine receptor , calmodulin , ryanodine receptor 2 , methionine , biochemistry , calcium , oxidative phosphorylation , calcium in biology , oxidative folding , amino acid , biology , microbiology and biotechnology , chemistry , cysteine , intracellular , medicine , enzyme
Mutations within the ubiquitous calcium‐sensing protein calmodulin (CaM) have been linked to congenital arrhythmia disorders including long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT). In cardiomyocytes, CaM is critical for regulating excitation‐contraction coupling by binding calcium as well as binding a diverse set of targets including the ryanodine receptor (RyR2) to regulate intracellular calcium levels. The vertebrate CaM primary sequence contains nine methionine (Met) amino acid residues which are highly conserved. All nine Met are susceptible to oxidation to methionine sulfoxide (MetO). These methionine residues are solvent‐exposed upon binding calcium and facilitate CaM binding its targets. CaM also contains a potential PEST sequence, an internal signal for rapid proteolytic degradation. We have investigated the oxidative and proteolytic susceptibility of four calmodulinopathy mutants: D96V and D130G, which are linked to LQTS and N54I and N98S, which are associated with CPVT. The goal of this research is to establish a correlation of CaM disease mutants and oxidative susceptibility, with an emphasis on the compounding and detrimental functional and structural effects these two types of modifications may cause. Support or Funding Information This work is supported by a NIH grant AG26160 to DDT and a Minnesota State University, Mankato Undergraduate Research Center Foundation Grant to JJ.