Synaptotagmin II. A Novel Differentially Distributed Form of Synaptotagmin

Synaptotagmin is a synaptic vesicle membrane protein with properties suggestive of a role in synaptic vesicle exocytosis (Perin, M. S., Fried, V. A., Mignery, G. A., Jahn, R., and Südhof, T. C. (1990) Nature 345, 260-263). Here, we report the structure of a novel form of synaptotagmin named synaptotagmin II that is highly homologous to the originally described synaptotagmin, now referred to as synaptotagmin I. Synaptotagmins I and II exhibit the same overall structure, containing a small intravesicular sequence that is glycosylated, a single transmembrane region, and a large carboxyl-terminal cytoplasmic sequence that includes two copies of an internal repeat homologous to the regulatory region of protein kinase C. The homology between synaptotagmins I and II is not uniformly distributed across the molecule but is highest in their carboxyl-terminal regulatory repeats (88% sequence identity) and lowest in their amino-terminal intravesicular sequences (46% sequence identity). RNA blots demonstrate complementary patterns of expression for synaptotagmins I and II, with synaptotagmin I preferentially expressed in rostral, phylogenetically younger brain regions, and synaptotagmin II predominantly expressed in caudal, phylogenetically older brain regions. With this description of two forms of synaptotagmin, all major synaptic vesicle proteins implicated in membrane traffic have now been shown to be present in several isoforms with differential distributions, suggesting that this is a general organizational principle of the mammalian brain.