National Center for
4IHB: X-RAY STRUCTURE OF THE canonical C2A DOMAIN FROM HUMAN DYSFERLIN
Alternate splicing of dysferlin C2A confers Ca(2)(+)-dependent and Ca(2)(+)-independent binding for membrane repair
Structure (2014) 22 p.104-115
Dysferlin plays a critical role in the Ca(2)(+)-dependent repair of microlesions that occur in the muscle sarcolemma. Of the seven C2 domains in dysferlin, only C2A is reported to bind both Ca(2)(+) 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 Ca(2)(+)-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.