Effect of Disease Mutants in Calmodulin on Oxidation, Binding and Degradation

Presenter Information

Jordan Julian, Minnesota State University, Mankato

Location

CSU Ballroom

Start Date

2-4-2019 10:00 AM

End Date

2-4-2019 11:30 AM

Student's Major

Chemistry and Geology

Student's College

Science, Engineering and Technology

Mentor's Name

Rebecca Moen

Mentor's Department

Chemistry and Geology

Mentor's College

Science, Engineering and Technology

Description

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease that causes episodic syncope and sudden cardiac arrest, particularly in infants. Various amino acid point mutations, including N54I and N97S, in the protein calmodulin (CaM) are the thought to be the primary cause of the genetic disease. Calmodulin is a key protein in calcium binding and signaling in all human muscles. CaM's impaired binding to both calcium ions as well as the ryanodine receptor (RyR2) in heart muscle is thought to be the primary cause of CPVT. In addition to disease-causing mutations, CaM has also been shown be highly susceptible to oxidation, particularly at its nine methionine residues. Oxidation of these side chains reduce the binding ability of CaM to RyR2 and calcium ions. The degradation of CaM is also affected by the oxidation of these methionine side chains and has not been fully studied. The reduced binding affinity of mutant CaM when paired with oxidation can be observed through its binding to RyR2 with the analysis of tryptophan fluorescence. The point mutations effects on the protein can be further observed through the proteasomal degradation of both the mutant and its oxidized form.