The membrane fusion enigma: SNAREs, Sec1/Munc18 proteins, and their accomplices--guilty as charged?
Neurotransmitter release is governed by proteins that have homo-logs in most types of intracellular membrane fusion, including the Sec1/Munc18 protein Munc18-1 and the SNARE proteins syntaxin-1, synaptobrevin/VAMP, and SNAP-25. The SNAREs initiate fusion by forming tight SNARE complexes that bring the vesicle and plasma membranes together. SNARE maintenance in a functional state depends on two chaperone systems (Hsc70/αCSP/SGT and synuclein); defects in these systems lead to neurodegeneration. Munc18-1 binds to an autoinhibitory closed conformation of syntaxin-1, gating formation of SNARE complexes, and also binds to SNARE complexes, which likely underlies the crucial function of Munc18-1 in membrane fusion by an as-yet unclear mechanism. Syntaxin-1 opening is mediated by Munc13s through their MUN domain, which is homologous to diverse tethering factors and may also have a general role in fusion. MUN domain activity is likely modulated in diverse presynaptic plasticity processes that depend on Ca(2+) and RIM proteins, among others.
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. jose@arnie.swmed.edu
Josep
J
Rizo
Thomas C
TC
Südhof
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008561:Membrane Fusion; D008958:Models, Molecular; D018832:Molecular Chaperones / Q000378:metabolism / Q000502:physiology; D051938:Munc18 Proteins / Q000378:metabolism / Q000502:physiology*; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D050600:SNARE Proteins / Q000378:metabolism / Q000502:physiology*
D018832:Molecular Chaperones; D051938:Munc18 Proteins; D050600:SNARE Proteins