The AD3 locus of synaptotagmin-1 C2 domains modulates domain stability.

Synaptotagmin-1 (syt1) functions as the Ca-dependent sensor that triggers the rapid and synchronous release of neurotransmitters from neurotransmitter-containing vesicles during neuronal exocytosis. The syt1 protein has two homologous tandem C2 domains that interact with phospholipids in a Ca-dependent manner. Despite the crucial role of syt1 in exocytosis, the precise interactions between Ca, syt1, and phospholipids are not fully understood.

Structural Basis for the Distinct Membrane Binding Activity of the Homologous C2A Domains of Myoferlin and Dysferlin.

Dysferlin has been implicated in acute membrane repair processes, whereas myoferlin's activity is maximal during the myoblast fusion stage of early skeletal muscle cell development. Both proteins are similar in size and domain structure; however, despite the overall similarity, myoferlin's known physiological functions do not overlap with those of dysferlin. Here we present for the first time the X-ray crystal structure of human myoferlin C2A to 1.

FerA is a Membrane-Associating Four-Helix Bundle Domain in the Ferlin Family of Membrane-Fusion Proteins.

Ferlin proteins participate in such diverse biological events as vesicle fusion in C. elegans, fusion of myoblast membranes to form myotubes, Ca-sensing during exocytosis in the hair cells of the inner ear, and Ca-dependent membrane repair in skeletal muscle cells. Ferlins are Ca-dependent, phospholipid-binding, multi-C2 domain-containing proteins with a single transmembrane helix that spans a vesicle membrane.

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

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).