SNARE complex · Grey Matter

The SNARE complex is the bundle of three proteins that pulls a synaptic vesicle onto the membrane of the terminal and fuses the two, and it is the motor of transmitter release: without it, vesicles dock but cannot open.

SNARE complex. The SNARE complex is the bundle of three proteins that pulls a synaptic vesicle onto the membrane of the terminal and fuses the two, and it is the motor of transmitter release: without it, vesicles dock but cannot open.

One protein comes from the vesicle, synaptobrevin (also called VAMP2), and two from the terminal membrane, syntaxin-1 and SNAP-25. Each contributes coiled helices (SNAP-25 two, the others one each), and the four helices wind together from the end farthest from the membranes toward them, like a zipper. The zipping releases energy that drags the vesicle and the plasma membrane into contact; partial zipping holds the vesicle primed, and the final step, triggered by calcium binding to synaptotagmin, opens a fusion pore through which the transmitter escapes. Helper proteins (Munc18, Munc13, complexin) organise the assembly and hold the half-zipped state.

After fusion the bundle is pulled apart by an ATP-using enzyme (NSF with its adaptor SNAPs), so every round of release has an energy cost and the proteins are reused.

Toxins cut it. Botulinum toxins cleave SNAP-25, syntaxin or synaptobrevin at the neuromuscular junction and block acetylcholine release (flaccid paralysis); tetanus toxin cleaves synaptobrevin in inhibitory spinal neurons and blocks their release (spastic paralysis).

The machinery is general. SNAREs drive membrane fusion throughout the cell, and the work that identified them was recognised by the 2013 Nobel Prize.

Two zip fasteners pulled together from the far end is the picture of the SNARE bundle.

The closer the teeth mesh to the cloth, the harder the two pieces are pressed into one.

Questions: How do the SNARE proteins and synaptotagmin divide the job of fusing a vesicle? The SNAREs supply the force: synaptobrevin on the vesicle and syntaxin and SNAP-25 on the terminal wind into a four-helix bundle that zips toward the membranes and pulls them together. Before a spike they are held half-zipped, with the vesicle primed but not fused, by helper proteins such as complexin and Munc13. Synaptotagmin supplies the timing: when calcium binds its two C2 domains, they insert into the membrane and push the half-zipped complex over the last step, opening a fusion pore. Remove the SNAREs and nothing fuses; remove synaptotagmin-1 and fusion still happens, but slowly and out of step with the spike. Why does botulinum toxin paralyse muscles while tetanus toxin makes them rigid? Both toxins are enzymes that cut SNARE proteins, and without intact SNAREs vesicles cannot fuse. Botulinum toxins act on motor nerve terminals at the neuromuscular junction, so acetylcholine release stops and the muscle goes limp; that is also how cosmetic and medical botulinum injections relax a chosen muscle. Tetanus toxin is carried backward up the motor axon into the spinal cord, where it cuts synaptobrevin in the inhibitory interneurons that release glycine and GABA onto motor neurons. With that brake gone the motor neurons fire unchecked and the muscles lock in spasm, so the same molecular cut gives opposite symptoms depending on which synapse loses it.