Sec1Munc18

Sec1/Munc18 (SM) proteins are a conserved family of regulatory factors essential for SNARE-mediated membrane fusion in eukaryotic cells. They regulate vesicle docking and fusion by interacting with syntaxins, the target membrane SNAREs, and thereby modulating the assembly of the SNARE complex.

A central feature of SM proteins is their interaction with syntaxin. In many cases, SM proteins bind to syntaxin in a closed conformation, concealing the SNARE motif and preventing premature fusion. Under appropriate cellular cues, SM proteins can help convert syntaxin to an open state and stabilize transition states that promote the assembly of the SNARE complex with SNAP-25 and VAMP, effectively priming vesicles for fusion. Depending on the context, SM proteins may act as chaperones, priming factors, or catalysts that regulate the timing and location of membrane fusion.

Diversity and localization vary across organisms. In yeast, Sec1p is required for exocytosis and general secretion. In animals, three main paralogs exist: Munc18-1 (STXBP1), Munc18-2 (STXBP2), and Munc18-3 (STXBP3), each with distinct tissue distribution and roles in neuronal, endocrine, and epithelial trafficking. SM proteins are found at various membranes, including the plasma membrane and intracellular organelles, reflecting participation in multiple trafficking routes such as exocytosis, endosome-to-lysosome fusion, and vacuolar fusion.

Structural studies show SM proteins adopt an arch-shaped, three-domain architecture that forms a binding pocket for syntaxin. Their function is tightly integrated with the broader SNARE machinery and regulation of vesicle fusion is essential for normal cellular communication and secretion. Mutations in SM proteins, particularly STXBP1, are associated with neurodevelopmental disorders and epileptic encephalopathies.