Article abstract
Nature Structural & Molecular Biology 15, 1160 - 1168 (2008)
Published online: 26 October 2008 | doi:10.1038/nsmb.1508
The Janus-faced nature of the C2B domain is fundamental for synaptotagmin-1 function
Mingshan Xue1,5, Cong Ma2,3,5, Timothy K Craig2,3, Christian Rosenmund1,4 & Josep Rizo2,3
Abstract
Synaptotagmin-1 functions as a Ca2+ sensor in neurotransmitter release and was proposed to act on both the synaptic vesicle and plasma membranes through interactions involving the Ca2+ binding top loops of its C2 domains and the Ca2+-independent bottom face of the C2B domain. However, the functional importance of the C2B domain bottom face is unclear. We now show that mutating two conserved arginine residues at the C2B domain bottom face practically abolishes synchronous release in hippocampal neurons. Reconstitution experiments reveal that Ca2+–synaptotagmin-1 can dramatically stimulate the rate of SNARE-dependent lipid mixing, and that the two-arginine mutation strongly impairs this activity. These results demonstrate that synaptotagmin-1 function depends crucially on the bottom face of the C2B domain and strongly support the notion that synaptotagmin-1 triggers membrane fusion and neurotransmitter release by bringing the vesicle and plasma membranes together, much like the SNAREs do but in a Ca2+-dependent manner.
- Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
- Department of Biochemistry University of Texas Southwestern Medical Center, Dallas, 6000 Harry Hines Boulevard, Dallas, Texas 75390, USA.
- Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, 6000 Harry Hines Boulevard, Dallas, Texas 75390, USA.
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.
- These authors contributed equally to this work.
Correspondence to: Christian Rosenmund1,4Josep Rizo2,3 e-mail: rosenmun@bcm.tmc.edu e-mail: jose@arnie.swmed.edu
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