| Munc18‑1, also known as syntaxin‑binding protein 1 (STXBP1), is a neuronal Sec1/Munc18 family protein that acts as a central organizer of the SNARE machinery controlling fast synaptic vesicle exocytosis at chemical synapses. The protein forms a multi‑domain arch that cradles syntaxin‑1 and presents distinct interaction surfaces for the closed conformation of syntaxin‑1, the N‑terminal syntaxin‑1 peptide, and assembled SNARE complexes, allowing it to stabilize syntaxin‑1, guide SNARE assembly, and remain associated during fusion. Munc18‑1 binds tightly to closed syntaxin‑1 and functions as a molecular chaperone that supports correct folding and axonal targeting of syntaxin‑1, which is required to maintain a competent pool of t‑SNAREs at presynaptic active zones and to prevent syntaxin mislocalization or degradation. During vesicle priming, Munc18‑1 cooperates with Munc13‑1 to open syntaxin‑1 and to template assembly of the ternary SNARE complex containing syntaxin‑1, SNAP‑25, and VAMP2/synaptobrevin‑2, so that the complex forms in a spatially and temporally controlled way that supports rapid Ca²⁺‑triggered fusion. Structural and functional analyses indicate that domain 3a of Munc18‑1, particularly helices 11 and 12, contacts the central region of the VAMP2 SNARE motif and aligns it with syntaxin‑1 and SNAP‑25, an interaction that is essential for efficient SNARE templating and for generating fusion‑competent trans‑SNARE complexes. The same scaffold stabilizes partially zippered SNARE assemblies at the plasma membrane and is proposed to help maintain vesicles in a primed state, ready for rapid membrane merger once synaptotagmin senses Ca²⁺ and releases the final constraints on fusion. Loss of Munc18‑1 function causes a near‑complete block of synaptic vesicle exocytosis and large dense‑core vesicle release, while graded reductions in Munc18‑1 reduce vesicle docking, cut the size of the readily releasable pool, and impair neurotransmitter output. Heterozygous de novo mutations in STXBP1 that alter Munc18‑1 stability or its interaction with syntaxin‑1 and SNARE complexes are linked to early infantile epileptic encephalopathy and related neurodevelopmental syndromes, where disturbed synaptic vesicle priming and reduced synchronous release correlate with epilepsy, intellectual disability, and movement abnormalities. |
