[PDF][PDF] Alternate splicing of dysferlin C2A confers Ca2+-dependent and Ca2+-independent binding for membrane repair

K Fuson, A Rice, R Mahling, A Snow, K Nayak… - Structure, 2014 - cell.com
K Fuson, A Rice, R Mahling, A Snow, K Nayak, P Shanbhogue, AG Meyer, GMI Redpath
Structure, 2014cell.com
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+ …
Summary
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 isoforms 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.
cell.com