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Elife. 2018 Jul 25;7. pii: e38981. doi: 10.7554/eLife.38981.

A mechanism for exocytotic arrest by the Complexin C-terminus.

Author information

1
Institute for Physiology, Center of Integrative Physiology and Molecular Medicine, University of Saarland, Homburg, Germany.
2
Institute for Medical Biochemistry and Molecular Biology, University of Saarland, Homburg, Germany.
3
Institute for Physiology, Otto-von-Guericke University, Magdeburg, Germany.
#
Contributed equally

Abstract

ComplexinII (CpxII) inhibits non-synchronized vesicle fusion, but the underlying mechanisms have remained unclear. Here, we provide evidence that the far C-terminal domain (CTD) of CpxII interferes with SNARE assembly, thereby arresting tonic exocytosis. Acute infusion of a CTD-derived peptide into mouse chromaffin cells enhances synchronous release by diminishing premature vesicle fusion like full-length CpxII, indicating a direct, inhibitory function of the CTD that sets the magnitude of the primed vesicle pool. We describe a high degree of structural similarity between the CpxII CTD and the SNAP25-SN1 domain (C-terminal half) and show that the CTD peptide lowers the rate of SDS-resistant SNARE complex formation in vitro. Moreover, corresponding CpxII:SNAP25 chimeras do restore complexin's function and even 'superclamp' tonic secretion. Collectively, these results support a so far unrecognized clamping mechanism wherein the CpxII C-terminus hinders spontaneous SNARE complex assembly, enabling the build-up of a release-ready pool of vesicles for synchronized Ca2+-triggered exocytosis.

KEYWORDS:

SNAREs; complexin; exocytotic arrest; mouse; neuroscience; neurotransmitter release; vesicle fusion

PMID:
30044227
PMCID:
PMC6075865
DOI:
10.7554/eLife.38981
[Indexed for MEDLINE]
Free PMC Article

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