SNARE (protein)

SNARE proteins (an acronym derived from "soluble NSF attachment receptor") are a large protein superfamily consisting of more than 60 members in yeast and mammalian cells.

The primary role of SNARE proteins is to mediate fusion of cellular transport vesicles with the cell membrane 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 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 with presynaptic membrane. These SNAREs are the targets of the bacterial neurotoxins responsible for botulism and tetanus.

SNARE structure
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.

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-$$\alpha$$-helix bundle, where one $$\alpha$$-helix is contributed by syntaxin-1, one $$\alpha$$-helix by synaptobrevin and two $$\alpha$$-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.

SNARE complexes
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.

Proposed mechanism of membrane fusion
Assembly of the SNAREs into the "trans" complexes likely bridges the apposed 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. To date, it has not been ultimately clarified whether the SNAREs are responsible solely for bringing membranes to apposition or whether they are the driving force for fusion.