TY - JOUR TI - The SNAP-25 linker supports fusion intermediates by local lipid interactions AU - Shaaban, Ahmed AU - Dhara, Madhurima AU - Frisch, Walentina AU - Harb, Ali AU - Shaib, Ali H AU - Becherer, Ute AU - Bruns, Dieter AU - Mohrmann, Ralf A2 - Brunger, Axel T A2 - Marder, Eve VL - 8 PY - 2019 DA - 2019/03/18 SP - e41720 C1 - eLife 2019;8:e41720 DO - 10.7554/eLife.41720 UR - https://doi.org/10.7554/eLife.41720 AB - SNAP-25 is an essential component of SNARE complexes driving fast Ca2+-dependent exocytosis. Yet, the functional implications of the tandem-like structure of SNAP-25 are unclear. Here, we have investigated the mechanistic role of the acylated “linker” domain that concatenates the two SNARE motifs within SNAP-25. Refuting older concepts of an inert connector, our detailed structure-function analysis in murine chromaffin cells demonstrates that linker motifs play a crucial role in vesicle priming, triggering, and fusion pore expansion. Mechanistically, we identify two synergistic functions of the SNAP-25 linker: First, linker motifs support t-SNARE interactions and accelerate ternary complex assembly. Second, the acylated N-terminal linker segment engages in local lipid interactions that facilitate fusion triggering and pore evolution, putatively establishing a favorable membrane configuration by shielding phospholipid headgroups and affecting curvature. Hence, the linker is a functional part of the fusion complex that promotes secretion by SNARE interactions as well as concerted lipid interplay. KW - exocytosis KW - SNARE complex KW - SNAP-25 KW - fusion pore KW - fusion triggering KW - chromaffin cells JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -