Structure of Human Synaptotagmin 1 C2AB in the Absence of Ca2+ Reveals a Novel Domain Association,

Biochemistry, 46 (45), 13041 -13048, 2007. 10.1021/bi701651k S0006-2960(70)01651-3
Web Release Date: October 23, 2007

Structure of Human Synaptotagmin 1 C2AB in the Absence of Ca²⁺ Reveals a Novel Domain Association

Kerry L. Fuson, Miguel Montes, J. Justin Robert, and R. Bryan Sutton*

Departments of Biochemistry and Molecular Biology and of Neuroscience and Cell Biology and Sealy Center for Structural Biology and Molecular Biophysics, The University of Texas Medical Branch, Galveston, Texas 77555

Received August 15, 2007

Revised Manuscript Received September 17, 2007

Abstract:

Release of neurotransmitter from synaptic vesicles requires the Ca²⁺/phospholipid-binding protein synaptotagmin 1. There is considerable evidence that cooperation between the tandem C2 domains of synaptotagmin is a requirement of regulated exocytosis; however, high-resolution structural evidence for this interaction has been lacking. The 2.7 Å crystal structure of the cytosolic domains of human synaptotagmin 1 in the absence of Ca²⁺ reveals a novel closed conformation of the protein. The shared interface between C2A and C2B is stabilized by a network of interactions between residues on the C-terminal -helix of the C2B domain and residues on loops 1-3 of the Ca²⁺-binding region of C2A. These interactions alter the overall shape of the Ca²⁺-binding pocket of C2A, but not that of C2B. Thus, synaptotagmin 1 C2A-C2B may utilize a novel regulatory mechanism whereby one C2 domain could regulate the other until an appropriate triggering event decouples them.

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