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© The Rockefeller University Press, 0021-9525/1999//589 $5.00
The Journal of Cell Biology, Volume 147, Number 3, , 1999 589-598

Crystal Structure of the Cytosolic C2a-C2b Domains of Synaptotagmin III

R. Bryan Sutton^a,b, James A. Ernst^c, and Axel T. Brunger^a,b

^a The Howard Hughes Medical Institute, Yale University, New Haven, Connecticut 06520
^b Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, Connecticut 06520
^c Department of Chemistry, Yale University, New Haven, Connecticut 06520
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520.(203) 432-6946(203) 432-6143

brunger{at}laplace.csb.yale.edu

Synaptotagmins are synaptic vesicle-associated, phospholipid-binding proteins most commonly associated with Ca⁺²-dependent exocytotic and Ca⁺²- independent endocytotic events. Synaptotagmin III is a 63.2-kD member of the synaptotagmin homology group; one of its characteristic properties is the ability to bind divalent cations and accessory proteins promiscuously. In the cytosolic portion of this protein, a flexible seven–amino acid linker joins two homologous C2 domains. The C2A domain binds to phospholipid membranes and other accessory proteins in a divalent cation-dependent fashion. The C2B domain promotes binding to other C2B domains, as well as accessory proteins independent of divalent cations. The 3.2 Å crystal structure of synaptotagmin III, residues 295–566, which includes the C2A and C2B domains, exhibits differences in the shape of the Ca⁺²-binding pocket, the electrostatic surface potential, and the stoichiometry of bound divalent cations for the two domains. These observations may explain the disparate binding properties of the two domains. The C2A and the C2B domains do not interact; synaptotagmin, therefore, covalently links two independent C2 domains, each with potentially different binding partners. A model of synaptotagmin's involvement in Ca⁺²-dependent regulation of membrane fusion through its interaction with the SNARE complex is presented.

Key Words: SNARE • synaptotagmin • C2 domains • crystallography • calcium-binding protein

© 1999 The Rockefeller University Press

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