Oxidative Susceptibility of Calmodulin Cardiac Arrhythmia Mutants

Abstract

The congenital arrhythmia disorder catecholaminergic polymorphic ventricular tachycardia (CPVT) is linked to missense mutations within the ubiquitous calcium‐sensing protein calmodulin (CaM). CaM plays various important roles in cellular and biological processes. 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. CaM is a unique protein, not only in its ability to bind four calcium ions through its N‐ and C‐terminal lobes but also due to its high number of methionine amino acid residues within its primary sequence. These methionine residues are solvent‐exposed upon binding calcium and facilitate CaM binding its targets. However, the location of these methionine residues make CaM extremely sensitive to oxidative modification by reactive oxygen species (ROS). ROS can directly interact with CaM, causing reversible oxidation of the methionine side chain to a methionine sulfoxide or irreversible oxidation to methionine sulfone. CaM also contains a potential PEST sequence, an internal signal for rapid proteolytic degradation. We have investigated the oxidative and proteolytic susceptibility of CPVT cardiac arrhythmia CaM mutants with particular focus on methionine oxidation.Support or Funding InformationNIH R37 AG026160This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.