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Proc Natl Acad Sci U S A. 2017 May 23;114(21):5455-5460. doi: 10.1073/pnas.1611506114. Epub 2017 May 10.

Entropic forces drive self-organization and membrane fusion by SNARE proteins.

Author information

1
Department of Chemical Engineering, Columbia University, New York, NY 10027.
2
Department of Physics, Columbia University, New York, NY 10027.
3
Department of Cellular and Molecular Physiology, Yale School of Medicine, Yale University, New Haven, CT 06520.
4
Nanobiology Institute, Yale University, West Haven, CT 06516.
5
Laboratoire de Neurophotonique, Centre National de la Recherche Scientifique, 75270 Paris, France.
6
Nanobiology Institute, Yale University, West Haven, CT 06516; james.rothman@yale.edu bo8@columbia.edu.
7
Department of Cell Biology, Yale School of Medicine, Yale University, New Haven, CT 06520.
8
Department of Chemical Engineering, Columbia University, New York, NY 10027; james.rothman@yale.edu bo8@columbia.edu.

Abstract

SNARE proteins are the core of the cell's fusion machinery and mediate virtually all known intracellular membrane fusion reactions on which exocytosis and trafficking depend. Fusion is catalyzed when vesicle-associated v-SNAREs form trans-SNARE complexes ("SNAREpins") with target membrane-associated t-SNAREs, a zippering-like process releasing ∼65 kT per SNAREpin. Fusion requires several SNAREpins, but how they cooperate is unknown and reports of the number required vary widely. To capture the collective behavior on the long timescales of fusion, we developed a highly coarse-grained model that retains key biophysical SNARE properties such as the zippering energy landscape and the surface charge distribution. In simulations the ∼65-kT zippering energy was almost entirely dissipated, with fully assembled SNARE motifs but uncomplexed linker domains. The SNAREpins self-organized into a circular cluster at the fusion site, driven by entropic forces that originate in steric-electrostatic interactions among SNAREpins and membranes. Cooperative entropic forces expanded the cluster and pulled the membranes together at the center point with high force. We find that there is no critical number of SNAREs required for fusion, but instead the fusion rate increases rapidly with the number of SNAREpins due to increasing entropic forces. We hypothesize that this principle finds physiological use to boost fusion rates to meet the demanding timescales of neurotransmission, exploiting the large number of v-SNAREs available in synaptic vesicles. Once in an unfettered cluster, we estimate ≥15 SNAREpins are required for fusion within the ∼1-ms timescale of neurotransmitter release.

KEYWORDS:

SNARE; entropic force; exocytosis; membrane fusion; neurotransmitter release

PMID:
28490503
PMCID:
PMC5448213
[Available on 2017-11-23]
DOI:
10.1073/pnas.1611506114
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