Dysferlin plays a critical role in the Ca2+-dependent repair of microlesions that occur in the muscle sarcolemma. Of the seven C2 domains in dysferlin, only C2A is reported to bind both Ca2+ and phospholipid, thus acting as a key sensor in membrane repair. Dysferlin C2A exists as two isoforms, the "canonical" C2A and C2A variant 1 (C2Av1). Interestingly, these isoforms have markedly different responses to Ca 2+ and phospholipid. Structural and thermodynamic analyses are consistent with the canonical C2A domain as a Ca2+-dependent, phospholipid-binding domain, whereas C2Av1 would likely be Ca 2+-independent under physiological conditions. Additionally, both isoforms display remarkably low free energies of stability, indicative of a highly flexible structure. The inverted ligand preference and flexibility for both C2A isoforms suggest the capability for both constitutive and Ca 2+-regulated effector interactions, an activity that would be essential in its role as a mediator of membrane repair.
Bibliographical noteFunding Information:
This work was supported by the Jain Foundation (to R.B.S. and S.T.C.); a National Science Foundation CAREER grant (MCB-0845676), the University of Minnesota Grant-in-Aid, and Funding for University of Minnesota Duluth Swenson College of Science and Engineering Faculty Research (to A.H.); and an Australian NHMRC CDF Fellowship (APP1048816; to S.T.C.). Portions of this research were carried out at the Stanford Synchrotron Radiation Lightsource (SSRL), a Directorate of SLAC National Accelerator Laboratory and an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Stanford University. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, the National Institutes of Health (NIH), National Institute of General Medical Sciences (NIGMS; including P41 GM103393), and the National Center for Research Resources (NCRR; P41 RR001209). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS, NCRR, or NIH. The authors thank Dr. Elliott Stollar for helpful discussion.