Alternate Splicing of Dysferlin C2A Confers Ca2+-Dependent and Ca2+-Independent Binding for Membrane Repair

作者：Fuson Kerry; Rice Anne; Mahling Ryan; Snow Adam; Nayak Kamakshi; Shanbhogue Prajna; Meyer Austin G; Redpath Gregory M I; Hinderliter Anne; Cooper Sandra T; Sutton R Bryan^*

来源：Structure, 2014, 22(1): 104-115.

DOI：10.1016/j.str.2013.10.001

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 Ca2+ 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 Ca2+-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 isofornns suggest the capability for both constitutive and Ca2+-regulated effector interactions, an activity that would be essential in its role as a mediator of membrane repair.

• 出版日期2014-1-7