TY - JOUR TI - Synergistic actions of v-SNARE transmembrane domains and membrane-curvature modifying lipids in neurotransmitter release AU - Dhara, Madhurima AU - Mantero Martinez, Maria AU - Makke, Mazen AU - Schwarz, Yvonne AU - Mohrmann, Ralf AU - Bruns, Dieter A2 - Brunger, Axel T A2 - Aldrich, Richard W VL - 9 PY - 2020 DA - 2020/05/11 SP - e55152 C1 - eLife 2020;9:e55152 DO - 10.7554/eLife.55152 UR - https://doi.org/10.7554/eLife.55152 AB - Vesicle fusion is mediated by assembly of SNARE proteins between opposing membranes. While previous work suggested an active role of SNARE transmembrane domains (TMDs) in promoting membrane merger (Dhara et al., 2016), the underlying mechanism remained elusive. Here, we show that naturally-occurring v-SNARE TMD variants differentially regulate fusion pore dynamics in mouse chromaffin cells, indicating TMD flexibility as a mechanistic determinant that facilitates transmitter release from differentially-sized vesicles. Membrane curvature-promoting phospholipids like lysophosphatidylcholine or oleic acid profoundly alter pore expansion and fully rescue the decelerated fusion kinetics of TMD-rigidifying VAMP2 mutants. Thus, v-SNARE TMDs and phospholipids cooperate in supporting membrane curvature at the fusion pore neck. Oppositely, slowing of pore kinetics by the SNARE-regulator complexin-2 withstands the curvature-driven speeding of fusion, indicating that pore evolution is tightly coupled to progressive SNARE complex formation. Collectively, TMD-mediated support of membrane curvature and SNARE force-generated membrane bending promote fusion pore formation and expansion. KW - neurotransmitter release KW - VAMP2 KW - membrane fusion KW - protein-lipid interplay KW - exocytosis KW - synaptobrevin2 JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -