title: Complexin clamps asynchronous release by blocking a secondary Ca(2+) sensor via its accessory α helix.
abstract: Complexin activates and clamps neurotransmitter release; impairing complexin function decreases synchronous, but increases spontaneous and asynchronous synaptic vesicle exocytosis. Here, we show that complexin-different from the Ca(2+) sensor synaptotagmin-1-activates synchronous exocytosis by promoting synaptic vesicle priming, but clamps spontaneous and asynchronous exocytosis-similar to synaptotagmin-1-by blocking a secondary Ca(2+) sensor. Activation and clamping functions of complexin depend on distinct, autonomously acting sequences, namely its N-terminal region and accessory α helix, respectively. Mutations designed to test whether the accessory α helix of complexin clamps exocytosis by inserting into SNARE-complexes support this hypothesis, suggesting that the accessory α helix blocks completion of trans-SNARE-complex assembly until Ca(2+) binding to synaptotagmin relieves this block. Moreover, a juxtamembranous mutation in the SNARE-protein synaptobrevin-2, which presumably impairs force transfer from nascent trans-SNARE complexes onto fusing membranes, also unclamps spontaneous fusion by disinhibiting a secondary Ca(2+) sensor. Thus, complexin performs mechanistically distinct activation and clamping functions that operate in conjunction with synaptotagmin-1 by controlling trans-SNARE-complex assembly.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University, 1050 Arastradero Road, Palo Alto, CA 94304-5543, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Yang
authors.forename: Yea Jin
authors.initials: YJ
authors.lastname: Kaeser-Woo
authors.forename: Zhiping P
authors.initials: ZP
authors.lastname: Pang
authors.forename: Wei
authors.initials: W
authors.lastname: Xu
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D005089:Exocytosis / Q000502:physiology*; D052139:Intracellular Calcium-Sensing Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary / Q000502:physiology*; D051381:Rats; D011922:Rats, Mutant Strains; D050600:SNARE Proteins / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology; D050863:Synaptotagmin I / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D052139:Intracellular Calcium-Sensing Proteins; D009419:Nerve Tissue Proteins; D050600:SNARE Proteins; D050863:Synaptotagmin I; C095992:complexin I