UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

SNARE machinery is optimized for ultrafast fusion

Manca, F; Pincet, F; Truskinovsky, L; Rothman, JE; Foret, L; Caruel, M; (2019) SNARE machinery is optimized for ultrafast fusion. Proceedings of the National Academy of Sciences , 116 (7) pp. 2435-2442. 10.1073/pnas.1820394116. Green open access

[thumbnail of 2435.full.pdf]
Preview
Text
2435.full.pdf - Published Version

Download (1MB) | Preview

Abstract

SNARE proteins zipper to form complexes (SNAREpins) that power vesicle fusion with target membranes in a variety of biological processes. A single SNAREpin takes about 1 s to fuse two bilayers, yet a handful can ensure release of neurotransmitters from synaptic vesicles much faster: in a 10th of a millisecond. We propose that, similar to the case of muscle myosins, the ultrafast fusion results from cooperative action of many SNAREpins. The coupling originates from mechanical interactions induced by confining scaffolds. Each SNAREpin is known to have enough energy to overcome the fusion barrier of 25–35 kBT; however, the fusion barrier only becomes relevant when the SNAREpins are nearly completely zippered, and from this state, each SNAREpin can deliver only a small fraction of this energy as mechanical work. Therefore, they have to act cooperatively, and we show that at least three of them are needed to ensure fusion in less than a millisecond. However, to reach the prefusion state collectively, starting from the experimentally observed half-zippered metastable state, the SNAREpins have to mechanically synchronize, which takes more time as the number of SNAREpins increases. Incorporating this somewhat counterintuitive idea in a simple coarse-grained model results in the prediction that there should be an optimum number of SNAREpins for submillisecond fusion: three to six over a wide range of parameters. Interestingly, in situ cryoelectron microscope tomography has very recently shown that exactly six SNAREpins participate in the fusion of each synaptic vesicle. This number is in the range predicted by our theory.

Type: Article
Title: SNARE machinery is optimized for ultrafast fusion
Open access status: An open access version is available from UCL Discovery
DOI: 10.1073/pnas.1820394116
Publisher version: https://doi.org/10.1073/pnas.1820394116
Language: English
Additional information: Copyright © The Author(s) 2019. This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
Keywords: SNARE, membrane fusion, protein folding, neurotransmitter release, muscle contraction
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Experimental Epilepsy
URI: https://discovery.ucl.ac.uk/id/eprint/10075231
Downloads since deposit
52Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item