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SNARE-mediated membrane fusion

Abstract

SNARE proteins have been proposed to mediate all intracellular membrane fusion events. There are over 30 SNARE family members in mammalian cells and each is found in a distinct subcellular compartment. It is likely that SNAREs encode aspects of membrane transport specificity but the mechanism by which this specificity is achieved remains controversial. Functional studies have provided exciting insights into how SNARE proteins interact with each other to generate the driving force needed to fuse lipid bilayers.

Key Points

  • Membrane fusion is important for various biological processes, including maintenance of the basic eukaryotic cellular organization. A vesicle fusion event involves many coordinated steps, such as targeting, tethering, priming and finally the triggering of the fusion event.

  • More than a hundred SNARE proteins have been found, and most of them can be assigned to three protein families ? the syntaxins, the VAMPs and the SNAP-25 family. The hallmark of all SNARE proteins is their coiled-coil domains.

  • SNARE proteins were initially thought to confer docking specificity. However, more recent functional data have shown that they are probably involved in fusion, rather than docking. It is likely that both SNARE-mediated fusion specificity and small GTPase Rab-mediated docking specificity ensure the fidelity of intracellular membrane transport.

  • SNAREs bind to each other to form a very stable four-stranded coiled-coil core complex. Neuronal core complexes are formed by one coil each from syntaxin and VAMP, and two coils from SNAP-25.

  • The regulation of the core complex formation is still largely unknown. Syntaxins have a large amino-terminal domain that interacts with its coil domain in the presence of the chaperone n-Sec1. After a conformational change that is triggered by unknown mechanisms, syntaxin opens up to allow the coil domain to assemble into the core complex, thus promoting fusion.

  • SNAREs on two membranes probably interact to form a partial and reversible complex before the final fusion trigger arrives to promote the full assembly of the core complex and membrane fusion.

  • The emerging model for membrane fusion is that vesicles dock with the help of Rab proteins and/or other factors, bringing SNAREs into proximity. The assembly of the SNARE core complex then directs the two membranes towards each other and creates membrane curvature and tension. Once the membranes are close enough, hemifusion occurs followed by fusion pore opening and expansion, leading to complete membrane fusion. SNARE proteins provide the driving force and stabilize the transition state in this reaction.

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Figure 1: Subcellular localization of mammalian SNAREs.
Figure 2: SNARE proteins form a four-helical bundle complex that drives membrane fusion.
Figure 3: SNARE domain structures and the interaction between syntaxin and its chaperone protein n-Sec1.
Figure 4: Molecular model of vesicle exocytosis.
Figure 5: Model of SNARE-mediated lipid fusion.

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Acknowledgements

We thank S. Scales for critically reading the manuscript and L. Gonzalez, S. Scales, B. Yang and R. Lin for the artwork in Figs 1, 2 and 4.

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Correspondence to Richard H. Scheller.

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DATABASE LINKS

NSF

syntaxin

SNAP-25

VAMP

α-SNAP

n-Sec1

calmodulin

synaptotagmin I

complexin

tomosyn

snapin

syntaphilin

Munc-13

Hyperlinked figure

STX1

Stx2

STX3

Stx4

STX5

STX6

STX7

STX8

STX10

STX11

STX13

STX16

STX17

STX18

VAMP1

VAMP2

VAMP3

VAMP4

VAMP5

VAMP7

VAMP8

SEC22

YKT6

SNAP23

SNAP29

SNAP25

GOS28

membrin

VTI1

BET1

FURTHER INFORMATION

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Glossary

PRESYNAPTIC

Pertaining to the neuron that transmits impulses to a synapse.

SYNAPTIC CLEFT

The extracellular space, typically 20 nm across, that separates the outer membrane of the presynaptic nerve ending from the postsynaptic membrane of the receiving cell in a synapse.

POSTSYNAPTIC

Pertaining to the neuron or the muscle cell that is on the efferent side of a synapse, which transduces signals away from the synapse.

PALMITOYLATION

Covalent attachment of a palmitate (16-carbon saturated fatty acid) to a cysteine residue through a thioester bond.

PC12 CELLS

A clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor and can synthesize, store and secrete catecholamines, much like sympathetic neurons. PC12 cells contain small, clear synaptic-like vesicles and larger dense core granules.

CRACKED PC12 CELL SYSTEM

Exocytosis assay in which PC12 cells are mechanically permeabilized by a ball homogenizer, and secretion of [3H] noradrenaline from dense core granules is reconstituted and measured.

DENSE CORE GRANULES

Large diameter (80?200 nm) secretory vesicles that have high electron density under electronmicroscopy. They usually contain neuropeptides or catecholamines.

CLOSTRIDIAL NEUROTOXINS

Bacterial toxins that potently block neurotransmitter release through their metalloproteolytic activity directed specifically towards SNARE proteins. Includes botulinum neurotoxins and tetanus toxin.

GOLGI TRANSPORT ASSAY

In vitro reconstitution assay consisting of isolated Golgi stacks, Mg-ATP and cytosol, where transport-coupled glycosylation is monitored.

EXOCYTOSIS

The discharge by a cell of intracellular materials into the extracellular space through fusion of vesicles (containing these materials) with the plasma membrane.

Fab FRAGMENT

Antigen-binding fragment of an immunoglobulin molecule. It is used when multimerization of antibodies caused by their Fc domains is not desirable.

CHROMAFFIN CELLS

They arise from the same precursors as sympathetic neurons, and can synthesize, store and secrete catacholamines. They are found in all vertebrates, at various bodily locations but especially in the medulla of the adrenal gland.

POLYISOPRENOID

Synthetic molecule consisting of varying numbers of branched five-carbon-atom moieties.

BOTULINUM NEUROTOXIN E

Clostridial neurotoxin that cleaves SNAP-25 carboxy-terminal coil.

EXOCYTIC BURST

Defined by Neher and colleagues as the initial burst of release occurring within a few hundred milliseconds after the stimulus (in the chromaffin cell system), which is probably due to exocytosis of secretory granules that are in a release-ready state. It can be further resolved into two kinetically distinct components.

FLUORESCENCE RESONANCE ENERGY TRANSFER

Process of energy transfer between two fluorophores. Can be used to determine the distance between two attachment positions within a macromolecule or between two molecules.

YEAST VACUOLAR FUSION SYSTEM

In vitro fusion assay that measures the homotypic fusion of vacuoles isolated from the yeast Saccharomyces cerevisiae using a colorimetric alkaline phosphatase assay.

SEA URCHIN EGG FUSION SYSTEM

In vitro fusion assay that measures the homotypic fusion of cortical vesicles isolated from sea urchin eggs upon addition of calcium, by measuring turbidity (A405).

TETANUS TOXIN

Clostridial neurotoxin that cleaves VAMP.

MEMBRANE CAPACITANCE MEASUREMENTS

Patch-clamp technique that allows indirect measurements of single exocytic events. The technique measures the increase in the capacitance (and therefore surface) of the plasma membrane that results from fusion of exocytic vesicles with the plasma membrane.

BOTULINUM NEUROTOXIN A

Clostridial neurotoxin that cleaves the SNAP-25 carboxy-terminal coil.

HEMIFUSION

Transient membrane fusion intermediate in which only the two proximal leaflets of the bilayer mix.

FREEZE?FRACTURE ELECTRON MICROSCOPY

A technique in which membrane samples are deep frozen and then fractured with the blade of a knife to reveal the internal structure of the membrane.

PATCH CLAMP

Technique whereby a very small electrode tip is sealed onto a patch of cell membrane, thereby making it possible to record the flow of current through individual ion channels or pores within the patch.

GAP JUNCTION

Communicating junction (permeant to molecules up to 1 kDa) between adjacent cells, which is composed of 12 connexin protein subunits, six of which form a connexon or hemichannel contributed by each of the coupled cells.

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Chen, Y., Scheller, R. SNARE-mediated membrane fusion. Nat Rev Mol Cell Biol 2, 98–106 (2001). https://doi.org/10.1038/35052017

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