Disease relevance of STXBP1

• Autoimmunity to munc-18 in Rasmussen's encephalitis [1].
• Using ligand blotting, we have shown that a 67-kDa yeast nuclear envelope protein (p67) recognizes synthetic peptides containing the yeast histone H2B or simian virus 40 large tumor antigen nuclear localization sequence [2].
• Mutations affecting VPS33B, a novel Sec1/Munc18 protein, have recently been linked to arthrogryposis, renal dysfunction, and cholestasis (ARC) syndrome [3].
• Increased phosphorylation of eukaryotic initiation factor 2alpha at the G2/M boundary in human osteosarcoma cells correlates with deglycosylation of p67 and a decreased rate of protein synthesis [4].
• The POEP activity of p67 is observed in different stress-related situations such as during heme-deficiency of reticulocytes, serum starvation and heat-shock of mammalian cells, vaccinia virus infection of mammalian cells, baculovirus infection of insect cells, mitosis, apoptosis, and possibly during normal cell growth [5].

Psychiatry related information on STXBP1

• Cdk5 and munc-18/p67 co-localization in early stage neurofibrillary tangles-bearing neurons in Alzheimer type dementia brains [6].

High impact information on STXBP1

• Munc18-1 accelerates fusion only for the cognate SNAREs for exocytosis, therefore enhancing fusion specificity [7].
• Our results indicate that CFTR function in epithelial cells is regulated by an interplay between syntaxin and Munc18 isoforms [8].
• Sec1/Munc-18 (SM) proteins are essential for intracellular membrane fusion reactions [9].
• Sec1/Munc18 proteins: mediators of membrane fusion moving to center stage [10].
• Munc-18 is an intracellular protein residing in presynaptic terminals, which is required for secretion of neurotransmitters [1].

Biological context of STXBP1

• The PKC-catalyzed phosphorylation of Munc-18 inhibits its interaction with syntaxin [11].
• Mints, Munc18-interacting proteins in synaptic vesicle exocytosis [12].
• We used fluorescence resonance energy transfer (FRET) to characterize the Munc18-1/syntaxin1A interaction in intact cells [13].
• The Sec1/Munc-18 (SM) family of proteins is required for vesicle fusion in eukaryotic cells and has been linked to the membrane-fusion proteins known as soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) [14].
• Furthermore, the effects of phorbol ester treatment on release kinetics were occluded in cells expressing phosphomimetic Munc18 [15].

Anatomical context of STXBP1

• Mint proteins are detectable only in brain and are composed of an N-terminal sequence that binds Munc18-1, a middle phosphotyrosine-binding domain, and two C-terminal PDZ domains thought to attach proteins to the plasma membrane [12].
• Genetic analyses in yeast, Caenorhabditis elegans, and Drosophila suggest that Munc-18 is essential for vesicle transport [11].
• Here, we show that recombinant Munc-18 is phosphorylated by conventional PKC in a Ca2+- and phospholipid-dependent manner in a cell-free system [11].
• Enhanced cyan fluorescent protein-Munc18-1 and a citrine variant of enhanced yellow fluorescent protein-syntaxin1A, or mutants of these proteins, were expressed as donor and acceptor pairs in human embryonic kidney HEK293-S3 and adrenal chromaffin cells [13].
• Regulation of Munc-18/syntaxin 1A interaction by cyclin-dependent kinase 5 in nerve endings [16].

Associations of STXBP1 with chemical compounds

• The first DOC2 C2 domain and most of munc18 are involved in direct interactions [17].
• Caenorhabditis elegans UNC-18 protein, homologous to yeast Sec1p, is important in neurotransmitter release, because the unc-18 mutation leads to severe paralysis and presynaptic acetylcholine (ACh) accumulation [18].
• Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms [8].
• Conserved components of the general fusion machinery that participate in synaptic vesicle exocytosis include soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), ATPase N-ethylmaleimide-sensitive factor, Munc18/nSec1, Rab3 GTPase, and the exocyst proteins [19].
• By decreasing the amount of cortical actin by Latrunculin A application, morphological docking can be restored artificially in docking-deficient munc18-1 null cells, but neither strong tethering nor fusion, demonstrating that morphological docking is not sufficient for secretion [20].
• Arachidonic acid is incapable of dissociating Munc18 from syntaxin 1 and, crucially, Munc18 remains associated with syntaxin 1 after arachidonic-acid-induced syntaxin 1 binding to synaptosomal-associated protein 25 kDa (SNAP25) [21].

Physical interactions of STXBP1

• Mint 1 and 2 are proteins that bind to munc18-1, an essential component of the synaptic vesicle fusion machinery, and are detectably expressed only in neurons [Okamoto and Südhof, J. Biol. Chem. 272, 31459-31464 (1997)] [22].
• We conclude that Munc18-1 allows for the formation of a complex between syntaxin and SNAP-25 that serves as an acceptor for vesicle-bound synaptobrevin and that thus represents an intermediate in the pathway towards exocytosis [23].

Other interactions of STXBP1

• Syntaxin 1A is delivered to the apical and basolateral domains of epithelial cells: the role of munc-18 proteins [24].
• Furthermore, overexpression of the ubiquitous isoform of munc-18, munc-18-2, is also capable of rescuing the transport of the t-SNARE [24].
• We conclude that like other Sec1/Munc18 proteins, VPS33B is involved in intracellular vesicle trafficking, being essential for the development of platelet alpha-granules but not for granule secretion [3].
• Thrombin ligation of protease-activated receptor-1 activated the phosphorylation of syntaxin 4 and Munc18c, which, in turn, disrupted the interaction between syntaxin 4 and Munc18 [25].
• We then applied this method to find plausible binding partners for proteins with uncharacterized binding specificities in the syntaxin/Unc-18 protein and TGF-beta/TGF-beta receptor families [26].

Analytical, diagnostic and therapeutic context of STXBP1

• Findings from immunofluorescence studies in PC12 cells have shown co-localization of Munc18-1 and Cdk5 with neurofilaments and microtubules [27].
• Using site-directed mutagenesis, we find that disruption of the closed conformation abolishes the ability of syntaxin to bind to munc18-1 and to inhibit secretion in PC12 cells [28].
• The induction of 53 genes was confirmed by using microarray analysis and quantitative real-time PCR: among these genes was MetAP2/p67, which encodes an activator of translational initiation and represents a validated target for inhibition of neovascularization [29].
• By contrast, p67-positive subclones stably expressed the antigen, and in situ hybridization to metaphase spreads demonstrated that amplified human DNA sequences were integrated into a specific marker chromosome [30].
• Using these enzyme forms, we have identified for the first time a direct role of residues within the N-terminal domain in modulating topoisomerase I catalysis, as revealed by significant differences between p67 and p91 in DNA binding, cleavage, strand rotation, and ligation [31].

References