Mechanism and function of synaptotagmin-mediated membrane apposition

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Abstract
Synaptotagmin-1 aggregates membranes in response to Ca2+. Using a variety of approaches, it was discovered that synaptotagmin-mediated membrane aggregation occurs through trans interactions between synaptotagmin molecules bound to different membranes. Synaptotagmin-regulated, SNARE-catalyzed fusion further requires synaptotagmin to drive the assembly of nonfusogenic syntaxin and SNAP25 into fusion-competent t-SNARE heterodimers. Synaptotagmin-1 is a Ca2+ sensor that triggers synchronous neurotransmitter release. The first documented biochemical property of synaptotagmin-1 was its ability to aggregate membranes in response to Ca2+. 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 Ca2+-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 Ca2+-bound synaptotagmin-1 and catalyzed by SNAREs.

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