Nature Structural & Molecular Biology 13, 209 - 217 (2006)
Published online: 19 February 2006; | doi:10.1038/nsmb1056
Close membrane-membrane proximity induced by Ca2+-dependent multivalent binding of synaptotagmin-1 to phospholipidsDemet Araç1, Xiaocheng Chen1, Htet A Khant2, Josep Ubach1, Steven J Ludtke2, Masahide Kikkawa3, Arthur E Johnson4, Wah Chiu2, Thomas C Südhof5
& Josep Rizo11
Departments of Biochemistry and Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA. 2
National Center for Macromolecular Imaging, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. 3
Department of Cell Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA. 4
Department of Medical Biochemistry and Genetics, Texas A&M University System Health Science Center, College Station, Texas 77843, USA. 5
Center for Basic Neuroscience, Department of Molecular Genetics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Correspondence should be addressed to Josep Rizo jose@arnie.swmed.edu Synaptotagmin acts as a Ca2+ sensor in neurotransmitter release through its two C2 domains. Ca2+-dependent phospholipid binding is key for synaptotagmin function, but it is unclear how this activity cooperates with the SNARE complex involved in release or why Ca2+ binding to the C2B domain is more crucial for release than Ca2+ binding to the C2A domain. Here we show that Ca2+ induces high-affinity simultaneous binding of synaptotagmin to two membranes, bringing them into close proximity. The synaptotagmin C2B domain is sufficient for this ability, which arises from the abundance of basic residues around its surface. We propose a model wherein synaptotagmin cooperates with the SNAREs in bringing the synaptic vesicle and plasma membranes together and accelerates membrane fusion through the highly positive electrostatic potential of its C2B domain.
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