SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) form a superfamily of small fusion proteins that are each characterized by a conserved domain termed the SNARE motif, a membrane-anchor domain and a more variable N-terminal domain.
SNAREs mediate membrane fusion through the spontaneous assembly of four complementary SNARE motifs. The assembly process leads to a tight connection between the fusing membranes and initiates membrane fusion.
SNARE assembly and disassembly are complex multistep reactions that are subject to several layers of regulation. These steps include: the control of SNARE reactivity in the membrane; the formation of SNARE subcomplexes that function as acceptors for the final assembly step; trans-SNARE complexes that bridge the opposing membranes before fusion; and the disassembly of SNARE complexes by the AAA+ (ATPases associated with various cellular activities) protein NSF (N-ethylmaleimide-sensitive factor).
Accessory proteins, such as SM (Sec1/Munc18-related) proteins, synaptotagmins and complexins, regulate parts of the SNARE cycle. Some of these proteins are conserved and seem to function on many SNAREs, whereas others seem to be specific for a few SNAREs. In most cases, their mechanism of action is only partially clear.
SNAREs function in all fusion reactions of the secretory pathway. Some function in only one trafficking step, whereas others are less specialized, which provides a healthy mix of robustness and flexibility.
Since the discovery of SNARE proteins in the late 1980s, SNAREs have been recognized as key components of protein complexes that drive membrane fusion. Despite considerable sequence divergence among SNARE proteins, their mechanism seems to be conserved and is adaptable for fusion reactions as diverse as those involved in cell growth, membrane repair, cytokinesis and synaptic transmission. A fascinating picture of these robust nanomachines is emerging.
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The authors are indebted to D. Fasshauer, E. Neher, S. Rizzoli and J. Sorensen for helpful comments and for critically reading the manuscript. We hope our colleagues will understand that, due to space limitations, only a fraction of the relevant work could be discussed. R.J. is supported by an award from the Gottfried Wilhelm Leibniz Program of the Deutsche Forschungsgemeinschaft and by a grant from the National Institutes of Health.
The authors declare no competing financial interests.
- AAA+ proteins
('ATPases associated with various cellular activities' proteins). A superfamily of proteins with one or two nucleotide-binding domains, which often form ring-like oligomers and function as chaperones in diverse cellular processes. They can unfold aggregates or tightly packed structures.
A post-translational modification of proteins in which a palmitate fatty acyl chain is covalently attached to a cysteine side chain by a thioester bond.
- CAAX box
A C-terminal motif of four amino acids — cysteine (C), two aliphatic amino acids (AA) and then any amino acid — (X) that is recognized as a substrate by farnesyltransferase and geranylgeranyltransferase I.
A post-translational modification of proteins in which a 15-carbon farnesyl residue is covalently attached to the cysteine of a CAAX-box motif by a thioester bond.
- Phox-homology (PX) domain
A conserved domain of ∼120 residues that is found in many proteins. PX domains preferably bind to phosphatidylinositol-3,4,5-trisphosphate, a polyphosphoinositide lipid that is enriched in endosomes and vacuoles.
(Coatomer protein complex-II). COPII assembles at the exit sites of the endoplasmic reticulum, which results in the formation of COPII-coated transport vesicles that are destined for the cis face of the Golgi apparatus or for an intermediate compartment.
- Adaptor protein-1 (AP1) complex
The AP1 complex, which is one of four structurally related protein complexes, forms a bridge between the clathrin coat and membrane components (cargo) during the formation of clathrin-coated vesicles at the trans-Golgi network.
- C2 domains
(Conserved region-2 of protein kinase C domains). Conserved and rigid domains that consist mainly of β-sheets and bind two to four Ca2+ ions. Their Ca2+ affinity is increased in the presence of acidic phospholipids, which leads to an association of C2 domains with membranes when the intracellular Ca2+ concentration rises.
Connexins, and the related pannexins and invertebrate innexins, are oligomeric membrane proteins that are found in the plasma membrane. They can interact in trans to form gap-junction channels between two cells.
A bacterial AAA+ (ATPases associated with various cellular activities) protein. It functions as an unfoldase that feeds its substrates into a tightly associated protease.
A bacterial AAA+ (ATPases associated with various cellular activities) protein. It functions in a complex with an associated caseinolytic protease in a manner similar to ClpA.
- Rab/Ypt (yeast protein transport) family
A family of Ras-related small GTPases. In their active GTP-bound form, members of this family can mediate the membrane attachment (tethering) of fusion partners through their interactions with specific effector proteins.
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Jahn, R., Scheller, R. SNAREs — engines for membrane fusion. Nat Rev Mol Cell Biol 7, 631–643 (2006). https://doi.org/10.1038/nrm2002
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