SNARE (protein)

Molecular machinery driving vesicle fusion in neuromediator release. The core SNARE complex is formed by four α-helices contributed by synaptobrevin, syntaxin and SNAP-25, synaptotagmin serves as a calcium sensor and regulates intimately the SNARE zipping

SNARE (an acronym derived from "SNAP (Soluble NSF Attachment Protein) REceptor") proteins are a large protein superfamily consisting of more than 60 members in yeast and mammalian cells.[1]

The primary role of SNARE proteins is to mediate vesicle fusion, that is, the exocytosis of cellular transport vesicles with the cell membrane at the porosome or with a target compartment (such as a lysosome).

SNAREs can be divided into two categories: vesicle or v-SNAREs , which are incorporated into the membranes of transport vesicles during budding, and target or t-SNAREs, which are located in the membranes of target compartments.

Recent classification however takes account of the structural features of the SNARE proteins and divides them into R-SNAREs and Q-SNAREs.

The best-studied SNAREs are those that mediate docking of synaptic vesicles with the presynaptic membrane. These SNAREs are the targets of the bacterial neurotoxins responsible for botulism and tetanus.

SNAREs are small, abundant and mostly plasma membrane-bound proteins. Although they vary considerably in structure and size, all share a segment in their cytosolic domain called a SNARE motif that consists of 60-70 amino acids that are capable of reversible assembly into tight, four-helix bundles called "trans"-SNARE complexes.

The readily-formed metastable "trans" complexes are composed of three SNAREs: syntaxin 1 and SNAP-25 resident in cell membrane and synaptobrevin (also referred to as vesicle-associated membrane protein or VAMP) anchored in the vesicular membrane.

In neuronal exocytosis, syntaxin and synaptobrevin are anchored in respective membranes by their C-terminal domains, whereas SNAP-25 is tethered to the plasma membrane via several cysteine-linked palmitoyl chains. The core SNARE complex is a four-α-helix bundle, where one α-helix is contributed by syntaxin-1, one α-helix by synaptobrevin and two α-helices are contributed by SNAP-25.

The plasma membrane-resident SNAREs have been shown to be present in distinct microdomains or clusters, the integrity of which is essential for the exocytotic competence of the cell.

Contents

SNARE complexes

Layering of the core SNARE complex. In the center is the zero hydrophilic ionic layer, flanked by hydrophobic leucine-zipper layers.

During membrane fusion, the SNARE proteins involved combine to form a SNARE complex. Depending on the stage of fusion of the host vesicles, these complexes may be referred to differently.

"Trans"-SNARE complexes are protein complexes composed of three SNARE proteins anchored in opposing (or trans) membranes prior to membrane fusion. During fusion, the membranes merge and SNARE proteins involved in complex formation after fusion are then referred to as a "cis"-SNARE complex, because they now reside in a single (or cis) resultant membrane.

R-SNAREs

R-SNAREs are proteins that contribute an arginine (R) residue in the formation of the zero ionic layer in the assembled core SNARE complex. One particular R-SNARE is synaptobrevin, which is located in the synaptic vesicles.

Q-SNAREs

Q-SNAREs are proteins that contribute a glutamine (Q) residue in the formation of the zero ionic layer in the assembled core SNARE complex. Q-SNAREs include syntaxin and SNAP-25.

Other components

The core SNARE complex is a 4-α-helix bundle.[2] Synaptobrevin and syntaxin contribute one α-helix each, while SNAP-25 participates with two α-helices (abbreviated as Sn1 and Sn2). The interacting amino acid residues that zip the SNARE complex can be grouped into layers. Each layer has 4 amino acid residues - one residue per each of the 4 α-helices. In the center of the complex is the zero ionic layer composed of one arginine (R) and three glutamine (Q) residues , and it is flanked by leucine zippering. Layers '-1', '+1' and '+2' at the centre of the complex most closely follow ideal leucine-zipper geometry and aminoacid composition.[3]

The zero ionic layer is composed of R56 from VAMP-2, Q226 from syntaxin-1A, Q53 from Sn1 and Q174 from Sn2, and is completely buried within the leucine-zipper layers. The positively charged guanidino group of the arginine (R) residue interact with the carboxyl groups of each of the three glutamine (Q) residues.

The flanking leucine-zipper layers act as a water-tight seal to shield the ionic interactions from the surrounding solvent. Exposure of the zero ionic layer to the water solvent by breaking the flanking leucine zipper leads to instability of the SNARE complex and is the putative mechanism by which α-SNAP and NSF recycle the SNARE complexes after the completion of synaptic vesicle exocytosis.

Proposed mechanism of membrane fusion

Assembly of the SNAREs into the "trans" complexes likely bridges the opposing lipid bilayers of membranes belonging to cell and secretory granule, bringing them in proximity and inducing their fusion. The influx of calcium into the cell triggers the completion of the assembly reaction, which is mediated by an interaction between the putative calcium sensor, synaptotagmin, with membrane lipids and/or the partially assembled SNARE complex.

According to the "zipper" hypothesis, the complex assembly starts at the N-terminal parts of SNARE motifs and proceeds towards the C-termini that anchor interacting proteins in membranes. Formation of the "trans"-SNARE complex proceeds through an intermediate complex composed of SNAP-25 and syntaxin-1, which later accommodates synaptobrevin-2 (the quoted syntaxin and synaptobrevin isotypes participate in neuronal neuromediator release).

Based on the stability of the resultant cis-SNARE complex, it has been postulated that energy released during the assembly process serves as a means for overcoming the repulsive forces between the membranes. There are several models that propose explanation of a subsequent step – the formation of stalk and fusion pore, but the exact nature of these processes remains debated. A recent in vitro single-molecule content-mixing study showed that yeast SNARE complex is enough to expand fusion pores.[4]

References

  1. ^ Gerald K (2002). "Cell and Molecular Biology (4th edition)". John Wiley & Sons, Inc.. 
  2. ^ Sutton RB, Fasshauer D, Jahn R, Brünger AT (1998). "Crystal structure of a SNARE complex involved in synaptic exocytosis at 2.4 Å resolution". Nature 395 (6700): 347–353. doi:10.1038/26412. PMID 9759724. http://atb.slac.stanford.edu/public/papers.php?sendfile=66. 
  3. ^ Fasshauer D, Sutton RB, Brunger AT, Jahn R (1998). "Conserved structural features of the synaptic fusion complex: SNARE proteins reclassified as Q- and R-SNAREs". Proceedings of the National Academy of Sciences 95 (26): 15781–15786. doi:10.1073/pnas.95.26.15781. PMC 28121. PMID 9861047. http://www.pnas.org/cgi/content/full/95/26/15781. 
  4. ^ Diao J et al. (2010). "A single-vesicle content mixing assay for SNARE-mediated membrane fusion". Nature Communications 1 (5): 54. doi:10.1038/ncomms1054. http://www.nature.com/ncomms/journal/v1/n5/pdf/ncomms1054.pdf. 

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