title: Molecular mechanism of the synaptotagmin-SNARE interaction in Ca2+-triggered vesicle fusion.
abstract: In neurons, SNAREs, synaptotagmin and other factors catalyze Ca(2+)-triggered fusion of vesicles with the plasma membrane. The molecular mechanism of this process, especially the interaction between synaptotagmin and SNAREs, remains an enigma. Here we characterized this interaction by single-molecule fluorescence microscopy and crystallography. The two rigid Ca(2+)-binding domains of synaptotagmin 3 (Syt3) undergo large relative motions in solution. Interaction with SNARE complex amplifies a particular state of the two domains that is further enhanced by Ca(2+). This state is represented by the first SNARE-induced Ca(2+)-bound crystal structure of a synaptotagmin fragment containing both domains. The arrangement of the Ca(2+)-binding loops of this structure of Syt3 matches that of SNARE-bound Syt1, suggesting a conserved feature of synaptotagmins. The loops resemble the membrane-interacting loops of certain viral fusion proteins in the postfusion state, suggesting unexpected similarities between both fusion systems.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University, Stanford, California, USA.
authors.forename: Marija
authors.initials: M
authors.lastname: Vrljic
authors.forename: Pavel
authors.initials: P
authors.lastname: Strop
authors.forename: James A
authors.initials: JA
authors.lastname: Ernst
authors.forename: R Bryan
authors.initials: RB
authors.lastname: Sutton
authors.forename: Steven
authors.initials: S
authors.lastname: Chu
authors.forename: Axel T
authors.initials: AT
authors.lastname: Brunger
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D018360:Crystallography, X-Ray; D031541:Fluorescence Resonance Energy Transfer; D008954:Models, Biological; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary / Q000235:genetics / Q000502:physiology; D051381:Rats; D050600:SNARE Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D050863:Synaptotagmin I / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D050600:SNARE Proteins; D050863:Synaptotagmin I; D002118:Calcium