Disease relevance of Stxbp1

• To investigate whether p67 is essential for the survival of mammalian cells, the basal level of p67 was lowered from rat tumor hepatoma cells using antisense approach [1].
• We show that a soluble Escherichia coli recombinant version of p67 (p67(635)), in which a prokaryotic signal peptide replaces the eukaryotic one, confers protection comparable to that induced by the full-length molecule, but is unstable [2].
• Recombinant p67 is, therefore, a candidate antigen for development of an anti-sporozoite vaccine for East Coast fever in cattle [3].

High impact information on Stxbp1

• Three-dimensional structure of the neuronal-Sec1-syntaxin 1a complex [4].
• Our data suggest that Munc-18 is a previously unidentified essential component of the synaptic vesicle fusion protein complex [5].
• Control of fusion pore dynamics during exocytosis by Munc18 [6].
• Here, in adrenal chromaffin cells, we expressed a Munc18 mutant with reduced affinity for syntaxin, which specifically modified the kinetics of single-granule exocytotic release events, consistent with an acceleration of fusion pore expansion [6].
• All vesicle transport steps also have an essential requirement for a member of the Sec1 protein family, including the neuronal Munc18-1 (also known as nSec1) in regulated exocytosis [6].

Biological context of Stxbp1

• These results support the hypothesis that Sec1 proteins function as syntaxin chaperons during vesicle docking, priming, and membrane fusion [7].
• Pancreatic beta-cell protein granuphilin binds Rab3 and Munc-18 and controls exocytosis [8].
• We have now characterized a new Munc-18 isoform, Munc-18-2, that exhibits 63% amino acid sequence identity with Munc-18-1 [9].
• We propose that p67, by virtue of its regulation of Cdk5, participates in the dynamics of axonal architecture through the modulation of phosphorylation of cytoskeletal components [10].
• The presence of both nuclear import and export signals in Munc18-1 primary structure corroborates its nuclear localization and makes it a putative shuttle protein between nuclear and cytoplasmic compartments, the precise physiological relevance of which needs to be elucidated [11].

Anatomical context of Stxbp1

• Granuphilins were found to bind to two components of the secretory machinery of pancreatic beta-cells, the small GTP-binding protein Rab3 and the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE)-binding protein Munc-18 [8].
• The mSec1/Munc-18 may be a receptor protein for syntaxin 1A on the transmitter vesicles mediating their interaction with the plasma membrane in docking and fusion [12].
• In view of the postulated role of Munc-18 in secretory vesicle docking, our data suggest that granuphilins may also be involved in this process [8].
• In chromaffin cells, the mammalian Sec1p homologue is a syntaxin 1A-binding protein associated with chromaffin granules [12].
• An anti-peptide antiserum directed against the n-Sec1 carboxyl terminus detects a 68-kDa protein in rat brain cytosol and membranes, but not in peripheral tissues [13].

Associations of Stxbp1 with chemical compounds

• p67, a cellular glycoprotein, protects eIF2alpha from phosphorylation by inhibitory kinases such as double-stranded RNA dependent eIF2 kinase, PKR, and heme-controlled repressor and thus promotes protein synthesis in mammalian cells [1].
• Arachidonic acid allows SNARE complex formation in the presence of Munc18 [14].
• Here we identify two other presynaptic proteins nitrated by peroxynitrite, Munc-18 and SNAP25, both of which are involved in sequential steps leading to vesicle exocytosis [15].
• Ethanol induced changes in cyclin-dependent kinase-5 activity and its activators, P35, P67 (Munc-18) in rat brain [16].
• The guanylate binding proteins, GBPs, are a family of interferon-induced GTP-binding proteins that include the rat p67 [17].

Physical interactions of Stxbp1

• Finally, larger fragments of syntaxin 1A that strongly bind to Munc18-1 but do not readily assemble into SNARE complexes had no effect on exocytosis in permeabilized PC12 cells [18].

Regulatory relationships of Stxbp1

• Exogenously expressed p67 stimulated Cdk5 kinase activity in vitro in a dose-dependent manner and when presented as an affinity matrix, selectively adsorbed Cdk5 from a cleared rat brain homogenate [10].

Other interactions of Stxbp1

• When recombinant taxilin was incubated with the extract from the rat brain crude membrane fraction, recombinant taxilin bound to syntaxin-1s free of at least VAMP2, SNAP-25, and Munc18 [19].
• In contrast, deletion of the transmembrane domain potentiates SNAP-25 and rbSec1A/nsec-1/munc18 binding [20].
• Our data indicate that the production of PI(4,5)P(2) is necessary for proper control of beta-cell secretion and suggest that at least part of the effect of PI on insulin exocytosis could be exerted through the activation of phospholipase D1, Ca(2+)-dependent activator protein for secretion 1, and Munc18-interacting protein 1 [21].
• Furthermore, Munc18, synaptophysin, and high amounts of the isoforms I and II of synaptotagmin were also found in DRM [22].
• Studies of signaling pathways involved in synaptic potentiation revealed that this blockade was due to a reduction of the phosphorylation by protein kinase C (PKC) of proteins that regulate SV recycling, such as myristoylated alanine-rich C kinase substrate (MARCKS) and Munc18-1/nSec1 [23].

Analytical, diagnostic and therapeutic context of Stxbp1

• The cDNA hybridizes to a 3.5-kb brain-specific mRNA by Northern blot analysis and encodes a protein of 593 amino acids (rbSec1) [24].
• In situ hybridization analysis of E18 rat embryos and adult rat brain demonstrated that p67 transcript expression is restricted to neural tissue [10].
• In the present study we have shown the presence of Munc18-1 in nuclear rich fraction from rat brain and confirmed the nuclear localization of this protein in PC12 cells and adult rat brain neurons by immunofluorescence and immunoelectron microscopy [11].
• Immunohistochemistry showed punctate Munc-18 immunoreactivity in the cytoplasm of rat pancreatic islet cells [25].
• By site-directed mutagenesis, (27)TSST(30) and (60)SGTS(63) clusters were substituted with (27)AAGA(30) and (60)AGAA(63) amino acid residues in full-length p67, and their EGFP fusions were constitutively expressed in rat tumor hepatoma cells (KRC-7) [26].

References