Effects of LQTS Mutations on Calmodulin Oxidation and Interaction with the Cardiac Ryanodine Receptor

Calmodulin (CaM) is a protein in the human body that binds calcium ions and regulation calcium concentration. It also plays a role in creating ion gradients and cell signaling pathways. This is accomplished by calcium pumps and calcium binding proteins. In my research, the emphasis is given to the role of CaM in calcium signaling in cardiac muscle. More than a dozen human CaM missense mutations have been described, all found in patients with severe cardiac arrhythmias (2). My research project will focus on two missense mutations in the calmodulin gene that result in Long QT Syndrome (LQTS), aspartic acid 95 to valine (D95V) and aspartic acid 129 to glycine (D129G). In addition to disease-causing mutations, CaM has been shown to be highly susceptibility to methionine oxidation (it contains no cysteines) which disrupts secondary structure, causes conformational disorder and affects hydrophobic interactions. This oxidation also impairs CaM\u27s ability to regulate RyR2 (3). I will investigate if these LQTS mutations in CaM make CaM more susceptible to oxidation as well as determine changes in the CaM/RyR2 binding interaction