Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 18, Issue 7, Pages 813-U92Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb.2075
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Funding
- Howard Hughes Medical Institute
- US National Institutes of Health (NIH) National Institute of Mental Health [MH061876]
- NIH National Institutes on Deafness and Other Communication Disorders [1K99DC011267-01]
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Synaptotagmin-1 is a Ca(2+) sensor that triggers synchronous neurotransmitter release. The first documented biochemical property of synaptotagmin-1 was its ability to aggregate membranes in response to Ca(2+). However, the mechanism and function of this process were poorly understood. Here we show that synaptotagmin-1-mediated vesicle aggregation is driven by trans interactions between synaptotagmin-1 molecules bound to different membranes. We found a strong correlation between the ability of Ca(2+)-bound synaptotagmin-1 to aggregate vesicles and to stimulate SNARE-mediated membrane fusion. Moreover, artificial aggregation of membranes-using non-synaptotagmin proteins-also efficiently promoted fusion of SNARE-bearing liposomes. Finally, using a modified fusion assay, we observed that synaptotagmin-1 drove the assembly of otherwise non-fusogenic individual t-SNARE proteins into fusion-competent heterodimers, independently of aggregation. Thus, membrane aggregation and t-SNARE assembly appear to be two key aspects of fusion reactions that are regulated by Ca(2+)-bound synaptotagmin-1 and catalyzed by SNAREs.
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