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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.

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


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.


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

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