Journal
ELIFE
Volume 11, Issue -, Pages -Publisher
eLIFE SCIENCES PUBL LTD
DOI: 10.7554/eLife.76356
Keywords
neurotransmitter release; molecular dynamics simulation; SNAREs; synaptotagmin; complexin; membrane fusion; None
Categories
Funding
- National Institute of Neurological Disorders and Stroke [R35 NS097333]
- Welch Foundation [I-1304]
- National Science Foundation [MCB-2111728]
- Natural Science Foundation of Shanghai [19ZR1473600]
- University of Texas at Austin
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Synaptic vesicles are prepared for fast neurotransmitter release upon calcium binding to Synaptotagmin-1. Molecular dynamics simulations suggest that SNARE complexes induce slow formation of membrane-membrane contact interfaces. The prepared state includes macromolecular assemblies of Synaptotagmin-1 and complexin bound to trans-SNARE complexes.
Synaptic vesicles are primed into a state that is ready for fast neurotransmitter release upon Ca2+-binding to Synaptotagmin-1. This state likely includes trans-SNARE complexes between the vesicle and plasma membranes that are bound to Synaptotagmin-1 and complexins. However, the nature of this state and the steps leading to membrane fusion are unclear, in part because of the difficulty of studying this dynamic process experimentally. To shed light into these questions, we performed all-atom molecular dynamics simulations of systems containing trans-SNARE complexes between two flat bilayers or a vesicle and a flat bilayer with or without fragments of Synaptotagmin-1 and/or complexin-1. Our results need to be interpreted with caution because of the limited simulation times and the absence of key components, but suggest mechanistic features that may control release and help visualize potential states of the primed Synaptotagmin-1-SNARE-complexin-1 complex. The simulations suggest that SNAREs alone induce formation of extended membrane-membrane contact interfaces that may fuse slowly, and that the primed state contains macromolecular assemblies of trans-SNARE complexes bound to the Synaptotagmin-1 C2B domain and complexin-1 in a spring-loaded configuration that prevents premature membrane merger and formation of extended interfaces, but keeps the system ready for fast fusion upon Ca2+ influx.
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