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| Title | SNARE disassembly requires Sec18/NSF side loading. |
|---|---|
| Journal, issue, pages | Nat Struct Mol Biol, Vol. 32, Issue 9, Page 1708-1720, Year 2025 |
| Publish date | Jul 2, 2025 |
 Authors | Yousuf A Khan / K Ian White / Richard A Pfuetzner / Bharti Singal / Luis Esquivies / Garvey Mckenzie / Fang Liu / Katherine DeLong / Ucheor B Choi / Elizabeth Montabana / Theresa Mclaughlin / William T Wickner / Axel T Brunger /   |
| PubMed Abstract | SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor) proteins drive membrane fusion at different cell compartments as their core domains zipper into a parallel four- ...SNARE (soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein receptor) proteins drive membrane fusion at different cell compartments as their core domains zipper into a parallel four-helix bundle. After fusion, these bundles are disassembled by the AAA+ (ATPase associated with diverse cellular activities) protein Sec18/NSF and its adaptor Sec17/α-SNAP to make them available for subsequent rounds of membrane fusion. SNARE domains are often flanked by C-terminal transmembrane or N-terminal domains. Previous structures of the NSF-α-SNAP-SNARE complex revealed binding to the D1 ATPase pore, posing a topological constraint as SNARE transmembrane domains would prevent complete substrate threading as suggested for other AAA+ systems. Using mass spectrometry in yeast cells, we show N-terminal SNARE domain interactions with Sec18, exacerbating this topological issue. We present cryo-electron microscopy (cryo-EM) structures of a yeast SNARE complex, Sec18 and Sec17 in a nonhydrolyzing condition, which show SNARE Sso1 threaded through the D1 and D2 ATPase rings of Sec18, with its folded, N-terminal Habc domain interacting with the D2 ring. This domain does not unfold during Sec18/NSF activity. Cryo-EM structures under hydrolyzing conditions revealed substrate-released and substrate-free states of Sec18 with a coordinated opening in the side of the ATPase rings. Thus, Sec18/NSF operates by substrate side loading and unloading topologically constrained SNARE substrates. |
 External links | Nat Struct Mol Biol / PubMed:40604310 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.99 - 10.88 Å |
| Structure data | EMDB-45883, PDB-9cru: EMDB-45885, PDB-9crx: EMDB-48826, PDB-9n22: EMDB-49380, PDB-9ng2: EMDB-49522, PDB-9nlu: EMDB-49524, PDB-9nlw: EMDB-49526, PDB-9nly: EMDB-49527, PDB-9nlz: EMDB-49528, PDB-9nm1: EMDB-49801, PDB-9nud: EMDB-49802, PDB-9nue: EMDB-49824, PDB-9nuz: EMDB-49825, PDB-9nv0: EMDB-49826, PDB-9nv1: EMDB-49831, PDB-9nv9: EMDB-49833, PDB-9nvd:  EMDB-70472: Y20S hydrolyzing Class 1 |
| Chemicals |  ChemComp-ADP:  ChemComp-ATP:  ChemComp-HOH:  ChemComp-MG: |
| Source |
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 Keywords | TRANSLOCASE / SNARE / NSF / Sec18 / AAA+ |
saccharomyces cerevisiae (brewer's yeast)
cricetulus griseus (Chinese hamster)