SNARE protein

SNARE proteins (soluble NSF attachment protein receptors) are a large protein family consisting of at least 24 members in yeasts and more than 60 members in mammalian and plant cells. The primary role of SNARE proteins is to mediate the fusion of vesicles with the target membrane; this notably mediates exocytosis, but can also mediate the fusion of vesicles with membrane-bound compartments (such as a lysosome). The best studied SNAREs are those that mediate the release of synaptic vesicles containing neurotransmitters in neurons. These neuronal SNAREs are the targets of the neurotoxins responsible for botulism and tetanus produced by certain bacteria.

Types 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 associated with nerve terminal membranes. Evidence suggests that t-SNAREs form stable subcomplexes which serve as guides for v-SNARE, incorporated into the membrane of a protein-coated vesicle, binding to complete the formation of the SNARE complex. Several SNARE proteins are located on both vesicles and target membranes, therefore, a more recent classification scheme takes into account structural features of SNAREs, dividing them into R-SNAREs and Q-SNAREs. Often, R-SNAREs act as v-SNAREs and Q-SNAREs act as t-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 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. Q-SNAREs are further classified as Qa-, Qb-, or Qc-SNAREs depending on their location in the four-helix bundle.

Occurrence Variants are known from yeasts, mammals, plants, Drosophila, and Caenorhabditis elegans.

Structure SNAREs are small, abundant, sometimes tail-anchored proteins which are often post-translationally inserted into membranes via a C-terminal transmembrane domain. Seven of the 38 known SNAREs, including SNAP-25, do not have a transmembrane domain and are instead attached to the membrane via lipid modifications such as palmitoylation. Tail-anchored proteins can be inserted into the plasma membrane, endoplasmic reticulum, mitochondria, and peroxisomes among other membranes, though any particular SNARE is targeted to a unique membrane. The targeting of SNAREs is accomplished by altering either the composition of the C-terminal flanking amino acid residues or the length of the transmembrane domain. Replacement of the transmembrane domain with lipid anchors leads to an intermediate stage of membrane fusion where only the two contacting leaflets fuse and not the two distal leaflets of the two membrane bilayer. Although SNAREs vary considerably in structure and size, they all share a segment in their cytosolic domain called a SNARE motif that consists of 60-70 amino acids and contains heptad repeats that have the ability to form coiled-coil structures. V- and t-SNAREs are capable of reversible assembly into tight, four-helix bundles called "trans"-SNARE complexes. In synaptic vesicles, 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 vesicle 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 trans-SNARE complex is a four- α {\displaystyle \alpha } -helix bundle, where one α {\displaystyle \alpha } -helix is contributed by syntaxin 1, one α {\displaystyle \alpha } -helix by synaptobrevin and two α {\displaystyle \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.

Membrane fusion

During membrane fusion, v-SNARE and t-SNARE proteins on separate membranes combine to form a trans-SNARE complex, also known as a "SNAREpin". Depending on the stage of fusion of the membranes, these complexes may be referred to differently. During fusion of trans-SNARE complexes, 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. After fusion, the cis-SNARE complex is bound and disassembled by an adaptor protein, alpha-SNAP. Then, the hexameric ATPase (of the AAA type) called NSF catalyzes the ATP-dependent unfolding of the SNARE proteins and releases them into the cytosol for recycling. SNAREs are thought to be the core required components of the fusion machinery and can function independently of additional cytosolic accessory proteins. This was demonstrated by engineering "flipped" SNAREs, where the SNARE domains face the extracellular space rather than the cytosol. When cells containing v-SNAREs contact cells containing t-SNAREs, trans-SNARE complexes form and cell-cell fusion ensues.

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