STRUCTURAL ANALYSIS OF THE IG59 DOMAIN OF OBSCURIN

Obscurin (800-900 kDa) is a giant muscle protein vital to muscle cell maintenance and organization. It is the only known connection between the contractile apparatus and the sarcoplasmic reticulum and also binds to specific cytoskeletal, signaling, or membrane-associated proteins. Mutations to obscurin and surrounding proteins are linked to cardiomyopathies and muscular dystrophies. A mutation (Arg4344Gln) in Ig58 of obscurin is found to be linked to hypertrophic cardiomyopathy (HCM), the most common cause of sudden cardiac death in adolescents. This mutation ablates obscurin binding to titin at the binding site of Ig58/59 of obscurin to ZIg9/10 of titin at the Z-disc of the sarcomere. In order for binding to occur, all four domains must be present. In an attempt to fully characterize both the wild-type and mutant protein structure here we describe initial efforts towards Ig58/59 structure determination using heteronuclear multidimensional NMR spectra. This will help to determine the molecular determinates that drive HCM. The HSQC spectra are unambiguously assigned for both the Ig58 and Ig59 domains, and the NOE-based secondary structure indicates two well-folded Ig-like domains.

Additional Abstract Information

Student(s): Tracy A. Caldwell

Department: Chemistry and Biochemistry

Faculty Advisor: Dr. Nathan T. Wright

Type: Oral

Year: 2014