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
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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.
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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.
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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.
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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.
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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.
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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.
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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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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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FURTHER INFORMATION
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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DOI: https://doi.org/10.1038/35052017
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