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2017 ; 114
(21
): 5455-5460
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Entropic forces drive self-organization and membrane fusion by SNARE proteins
#MMPMID28490503
Mostafavi H
; Thiyagarajan S
; Stratton BS
; Karatekin E
; Warner JM
; Rothman JE
; O'Shaughnessy B
Proc Natl Acad Sci U S A
2017[May]; 114
(21
): 5455-5460
PMID28490503
show ga
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.