Molecular mechanism underlying SNARE- mediated membrane fusion enlightened by all- atom molecular dynamics simulations

• 成果类型: Article
• 署名作者: Rizo, Josep; Sari, Levent; Jaczynska, Klaudia; Rosenmund, Christian; Lin, Milo M.
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-12375
• DOI: 10.1073/pnas.2321447121
• 发表日期: 2024-04-16
• 关键词: neurotransmitter release; 3-dimensional structure; juxtamembrane region; vesicle fusion; complex; exocytosis; pore; machinery; template; provides

摘要

The SNAP receptor (SNARE) proteins syntaxin-1, SNAP - 25, and synaptobrevin mediate neurotransmitter release by forming tight SNARE complexes that fuse synaptic vesicles with the plasma membranes in microseconds. Membrane fusion is generally explained by the action of proteins on macroscopic membrane properties such as curvature, elastic modulus, and tension, and a widespread model envisions that the SNARE motifs, juxtamembrane linkers, and C- terminal transmembrane regions of synaptobrevin and syntaxin-1 form continuous helices that act mechanically as semirigid rods, squeezing the membranes together as they assemble (zipper) from the N to the C termini. However, the mechanism underlying fast SNARE- induced membrane fusion remains unknown. We have used all - atom molecular dynamics simulations to investigate this mechanism. Our results need to be interpreted with caution because of the limited number and length of the simulations, but they suggest a model of membrane fusion that has a natural physicochemical basis, emphasizes local molecular events over general membrane properties, and explains extensive experimental data. In this model, the central event that initiates fast (microsecond scale) membrane fusion occurs when the SNARE helices zipper into the juxtamembrane linkers which, together with the adjacent transmembrane regions, promote encounters of acyl chains from both bilayers at the polar interface. The resulting hydrophobic nucleus rapidly expands into stalk - like structures that gradually progress to form a fusion pore, aided by the SNARE transmembrane regions and without clearly discernible intermediates. The propensity of polyunsaturated lipids to participate encounters that initiate fusion suggests that these lipids may be important for the high speed of neurotransmitter release.