title: Complexin cross-links prefusion SNAREs into a zigzag array.
abstract: Complexin prevents SNAREs from releasing neurotransmitters until an action potential arrives at the synapse. To understand the mechanism for this inhibition, we determined the structure of complexin bound to a mimetic of a prefusion SNAREpin lacking the portion of the v-SNARE that zippers last to trigger fusion. The 'central helix' of complexin is anchored to one SNARE complex, while its 'accessory helix' extends away at ~45° and bridges to a second complex, occupying the vacant v-SNARE binding site to inhibit fusion. We expected the accessory helix to compete with the v-SNARE for t-SNARE binding but found instead that the interaction occurs intermolecularly. Thus, complexin organizes the SNAREs into a zigzag topology that, when interposed between the vesicle and plasma membranes, is incompatible with fusion.
authors.affiliation: Department of Cell Biology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kümmel
authors.forename: Shyam S
authors.initials: SS
authors.lastname: Krishnakumar
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Radoff
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Claudio G
authors.initials: CG
authors.lastname: Giraudo
authors.forename: Frederic
authors.initials: F
authors.lastname: Pincet
authors.forename: James E
authors.initials: JE
authors.lastname: Rothman
authors.forename: Karin M
authors.initials: KM
authors.lastname: Reinisch
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D008561:Membrane Fusion / Q000502:physiology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary; D051381:Rats; D050827:Syntaxin 1 / Q000737:chemistry / Q000378:metabolism; D050988:Vesicle-Associated Membrane Protein 2 / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D009419:Nerve Tissue Proteins; C494213:Stx1a protein, rat; D050827:Syntaxin 1; C494807:VAMP2 protein, human; D050988:Vesicle-Associated Membrane Protein 2; C095992:complexin I