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Structural characterization of intermediates in Sec1/Munc18 protein-catalyzed SNARE assembly
Abigail E Stanton1, Isabella Midura1, Nanako Shirai1
1Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
The Journal of Biological Chemistry
|July 21, 2026
Summary
Sec1/Munc18 (SM) proteins are crucial for intracellular membrane fusion. This study reveals the structures of SM-SNARE complexes, detailing how SM proteins like Vps33 facilitate SNARE assembly through a dynamic nucleus.
Area of Science:
- Molecular Biology
- Cell Biology
- Structural Biology
Background:
- SNARE proteins mediate intracellular membrane fusion by forming complexes.
- Sec1/Munc18 (SM) proteins are essential cofactors that bind SNAREs during assembly.
Purpose of the Study:
- To determine the crystal structure of an endolysosomal SM-SNARE template complex.
- To elucidate the structural basis of early SNARE assembly steps mediated by SM proteins.
Main Methods:
- Crystal structure determination of SM-SNARE complexes.
- Alanine-scanning mutagenesis to probe protein-protein interactions.
Main Results:
- The crystal structure of Vps33 bound to R- and Qa-SNAREs (Nyv1 and Vam3) was determined.
- A dynamic SNARE assembly nucleus formed by SM protein and SNARE helices facilitates further assembly.
- A split binding mode of the R-SNARE Nyv1 was identified, with distinct N- and C-terminal interaction strengths.
Conclusions:
- Two early steps in SM-catalyzed endolysosomal SNARE assembly are defined.
- Conserved and divergent features of SM-mediated SNARE assembly pathways are highlighted.
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