Stxbp1 (Munc18-1, nSec1, rbSec1, p67) - manual literature synthesis (rat, P61765)

No deep-research API was available for this review. This synthesis was written by the
reviewer from the cached publications in publications/, the UniProt record
(Stxbp1-uniprot.txt) and PubMed/PMC look-ups. Each statement carries inline provenance.

Identity and family

• Rat Stxbp1 (UniProtKB P61765, RGD:3785, GeneID 25558), 594 aa, two splice isoforms
  (Munc18-1a, Munc18-1b). "Belongs to the STXBP/unc-18/SEC1 family" [UniProt CC SIMILARITY].
• Neuron- and neuroendocrine-enriched: "Brain and spinal cord. Highly enriched in axons."
  [UniProt CC TISSUE SPECIFICITY].
• Soluble protein that is cytosolic and recruited to membranes: "Membrane; Peripheral membrane
  protein." [UniProt CC SUBCELLULAR LOCATION]. Plasma-membrane recruitment depends on syntaxin-1:
  PMID:12093152.

Binding partners and binding modes

• Closed syntaxin-1 (binary complex, mode 1): crystal structure of the rat nSec1-syntaxin 1a
  complex PMID:10746715. Binds both
  syntaxin 1A and 1B PMID:12093152.
• Syntaxin-1 N-peptide (modes 2/3) PMID:18337752; crystal structure of Munc18-1 with
  the N-peptide PMID:21193638.
• Assembled SNARE complexes PMID:17301226; and membrane-anchored syntaxin-1/SNAP-25
  heterodimers PMID:18201107. Munc18-1 and complexin-1 bind simultaneously to SNARE complexes
  PMID:19255244.
• VAMP2 via helix 12 of domain 3a, the basis of its template activity PMID:24532794.
• Other partners (peripheral to the core function): Mint1/Mint2 (APBA1/2)
  PMID:9395480;
  Cdk5 and cytoskeletal proteins PMID:12963086; phospholipase D, which Munc18-1 inhibits
  PMID:14744865;
  Rab3A, which Munc18-1 helps dissociate from vesicles PMID:21689256; Cab45b
  PMID:17442889. Syntaxin 11 in mast cells PMID:23487749.

Mechanism: dual inhibitory and stimulatory roles in SNARE assembly

• Inhibitory: when bound to closed syntaxin-1 (and its N-peptide), Munc18-1 blocks SNARE complex
  formation [PMID:18337752 "When the syntaxin 1a N-peptide is bound to Munc18a, SNARE complex
  formation is blocked"; PMID:12093152 three-hybrid inhibition of syntaxin-VAMP complexes;
  PMID:26030875 "Munc18-1 strongly inhibits SNARE complex formation, whereas addition of either
  MUN* or MUN933 equally facilitates SNARE complex assembly"]. Munc13-1 MUN domain opens syntaxin-1
  and drives the transition from the Munc18-1/closed syntaxin complex to the SNARE complex
  PMID:26030875.
• Stimulatory/template: Munc18-1 domain 3a helix 12 templates VAMP2 and syntaxin, accelerating
  trans-SNARE (SNAREpin) assembly and liposome fusion PMID:24532794. In a
  GUV/SUV reconstitution, Syt1 docks vesicles first and Munc18-1 then accelerates SNAREpin assembly
  PMID:22810233. Munc18-1 shifts syntaxin toward
  an open state when associated with SNAP25 PMID:26876096.
• Chaperone of syntaxin-1: Munc18-1 stabilizes syntaxin-1 PMID:15935055 and supports its
  membrane delivery PMID:17543282;
  in its absence syntaxin-1 is retained in the ER PMID:26359495.

Physiological roles

• Synaptic vesicle priming and neurotransmitter release: lentiviral Munc18-1 rescues release in
  knockout neurons; point mutations that preserve closed-syntaxin binding but disrupt SNARE-complex
  binding "selectively impairs synaptic vesicle priming but not Ca(2+)-triggered fusion of primed
  vesicles" PMID:19255244.
• Neuroendocrine dense-core vesicle exocytosis (PC12, chromaffin): in Munc18-silenced PC12 cells
  stimulated exocytosis is lost and wild-type Munc18 fully rescues it; the syntaxin N-peptide
  (mode 2/3) interaction raises the fusion probability of a post-docking vesicle pool ~5-fold
  PMID:20801887. Mutants modelled on
  invertebrate/yeast SM alleles alter chromaffin exocytosis kinetics PMID:15563604.
• Non-neuronal regulated exocytosis (peripheral): mast-cell degranulation (with Munc18-2)
  PMID:23487749; human sperm acrosomal exocytosis PMID:23091057; platelets contain Munc18a but Munc18c dominates granule release
  PMID:12773094.
• Indirect/systemic: antisense knock-down in hypothalamus lowers glutamate release and delays
  puberty in female rats; hypothalamic expression rises with estrogen PMID:16951547.
• Unusual localizations: nuclear/perinuclear Munc18-1 in PC12 and brain neurons
  PMID:15869823; association with cytoskeletal elements PMID:12963086.

Disease context

Human STXBP1 haploinsufficiency causes developmental and epileptic encephalopathy
(STXBP1 encephalopathy); not reviewed here in detail since this is the rat entry.