munc18 proteins

Summary

Summary: A family of proteins involved in intracellular membrane trafficking. They interact with SYNTAXINS and play important roles in vesicular docking and fusion during EXOCYTOSIS. Their name derives from the fact that they are related to Unc-18 protein, C elegans.

Top Publications

  1. Peng R, Gallwitz D. Sly1 protein bound to Golgi syntaxin Sed5p allows assembly and contributes to specificity of SNARE fusion complexes. J Cell Biol. 2002;157:645-55 pubmed
    ..This indicates for the first time that a Sec1 family member contributes to the specificity of SNARE complex assembly. ..
  2. Agrawal A, Adachi R, Tuvim M, Yan X, Teich A, Dickey B. Gene structure and promoter function of murine Munc18-2, a nonneuronal exocytic Sec1 homolog. Biochem Biophys Res Commun. 2000;276:817-22 pubmed
    ..The region from +5 to -430 is more active than +5 to -800, suggesting upstream repressor elements. ..
  3. Saitsu H, Hoshino H, Kato M, Nishiyama K, Okada I, Yoneda Y, et al. Paternal mosaicism of an STXBP1 mutation in OS. Clin Genet. 2011;80:484-8 pubmed publisher
    ..3%, 8.7%, 11.9%, and 16.9% of alleles harbored the mutation, respectively. This is a first report of somatic mosaicism of an STXBP1 mutation, which has implications in genetic counseling of OS. ..
  4. Shuang R, Zhang L, Fletcher A, Groblewski G, Pevsner J, Stuenkel E. Regulation of Munc-18/syntaxin 1A interaction by cyclin-dependent kinase 5 in nerve endings. J Biol Chem. 1998;273:4957-66 pubmed
  5. Burkhardt P, Hattendorf D, Weis W, Fasshauer D. Munc18a controls SNARE assembly through its interaction with the syntaxin N-peptide. EMBO J. 2008;27:923-33 pubmed publisher
    ..This suggests that Munc18a controls the accessibility of syntaxin 1a to its partners, a role that might be common to all SM proteins. ..
  6. Koumandou V, Dacks J, Coulson R, Field M. Control systems for membrane fusion in the ancestral eukaryote; evolution of tethering complexes and SM proteins. BMC Evol Biol. 2007;7:29 pubmed
    ..However, the independent origin of the tethering complexes suggests a novel pattern for increasing complexity in the membrane trafficking system, in addition to the pattern of paralogous machinery elaboration seen thus far. ..
  7. Houng A, Polgar J, Reed G. Munc18-syntaxin complexes and exocytosis in human platelets. J Biol Chem. 2003;278:19627-33 pubmed
    ..In summary, Munc18 proteins bind to specific syntaxin isoforms in platelets despite the presence of other potential binding partners...
  8. Liu J, Ernst S, Gladycheva S, Lee Y, Lentz S, Ho C, et al. Fluorescence resonance energy transfer reports properties of syntaxin1a interaction with Munc18-1 in vivo. J Biol Chem. 2004;279:55924-36 pubmed
    ..We conclude that FRET imaging in living cells may allow correlated regulation of Munc18-1/syntaxin1A interactions to Ca(2+)-regulated secretory events. ..
  9. Tall G, Hama H, DeWald D, Horazdovsky B. The phosphatidylinositol 3-phosphate binding protein Vac1p interacts with a Rab GTPase and a Sec1p homologue to facilitate vesicle-mediated vacuolar protein sorting. Mol Biol Cell. 1999;10:1873-89 pubmed
    ..We propose that activated-Vps21p interacts with its effector, Vac1p, which interacts with Vps45p to regulate the Golgi to endosome SNARE complex. ..

More Information

Publications62

  1. Li Y, Schmitt H, Gallwitz D, Peng R. Mutations of the SM protein Sly1 resulting in bypass of GTPase requirement in vesicular transport are confined to a short helical region. FEBS Lett. 2007;581:5698-702 pubmed
    ..This indicates that alpha-20 in fungal Sly1p plays an important role in mediating Ypt/Rab-regulated Sly1p function in membrane fusion. ..
  2. Graham M, Handley M, Barclay J, Ciufo L, Barrow S, Morgan A, et al. A gain-of-function mutant of Munc18-1 stimulates secretory granule recruitment and exocytosis and reveals a direct interaction of Munc18-1 with Rab3. Biochem J. 2008;409:407-16 pubmed
  3. D Andrea Merrins M, Chang L, Lam A, Ernst S, Stuenkel E. Munc18c interaction with syntaxin 4 monomers and SNARE complex intermediates in GLUT4 vesicle trafficking. J Biol Chem. 2007;282:16553-66 pubmed
    ..Therefore, in contradiction to previous models, our data indicates that the conformational "opening" of syntaxin 4 rather than the dissociation of Munc18c is the critical event required for GLUT4 vesicle docking. ..
  4. Garcia E, McPherson P, Chilcote T, Takei K, De Camilli P. rbSec1A and B colocalize with syntaxin 1 and SNAP-25 throughout the axon, but are not in a stable complex with syntaxin. J Cell Biol. 1995;129:105-20 pubmed
    ..They also suggest that the function of rbSec1, syntaxin 1, and SNAP-25 is not restricted to synaptic vesicle exocytosis at the synapse. ..
  5. Barclay J. Munc-18-1 regulates the initial release rate of exocytosis. Biophys J. 2008;94:1084-93 pubmed
    ..Through these two late-stage functions, Munc-18-1 could act as a key protein involved in the presynaptic control of signaling strength and duration. ..
  6. Heeroma J, Roelandse M, Wierda K, van Aerde K, Toonen R, Hensbroek R, et al. Trophic support delays but does not prevent cell-intrinsic degeneration of neurons deficient for munc18-1. Eur J Neurosci. 2004;20:623-34 pubmed
    ..Second, trophic support delays but cannot prevent degeneration. Third, a cell-intrinsic yet unknown function of munc18-1 is essential for prolonged survival. ..
  7. Nicoletta J, Ross J, Li G, Cheng Q, Schwartz J, Alexander E, et al. Munc-18-2 regulates exocytosis of H(+)-ATPase in rat inner medullary collecting duct cells. Am J Physiol Cell Physiol. 2004;287:C1366-74 pubmed
  8. de Wit H, Walter A, Milosevic I, Gulyas Kovacs A, Riedel D, Sørensen J, et al. Synaptotagmin-1 docks secretory vesicles to syntaxin-1/SNAP-25 acceptor complexes. Cell. 2009;138:935-46 pubmed publisher
  9. Sudhof T, Rothman J. Membrane fusion: grappling with SNARE and SM proteins. Science. 2009;323:474-7 pubmed publisher
  10. Tellam J, McIntosh S, James D. Molecular identification of two novel Munc-18 isoforms expressed in non-neuronal tissues. J Biol Chem. 1995;270:5857-63 pubmed
    ..It is likely, based on these findings, that unique Munc-18/syntaxin interactions may play an important role in generating a combinatorial mechanism for the regulation of vesicle transport in mammalian cells. ..
  11. Martin Verdeaux S, Pombo I, Iannascoli B, Roa M, Varin Blank N, Rivera J, et al. Evidence of a role for Munc18-2 and microtubules in mast cell granule exocytosis. J Cell Sci. 2003;116:325-34 pubmed
    ..These findings suggest a role for Munc18-2 and the microtubule network in the regulation of secretory granule dynamics in mast cells. ..
  12. Riento K, Kauppi M, Keranen S, Olkkonen V. Munc18-2, a functional partner of syntaxin 3, controls apical membrane trafficking in epithelial cells. J Biol Chem. 2000;275:13476-83 pubmed
    ..While one of the mutants tested had no effect, one inhibited and one enhanced the apical transport of HA. This implies that Munc18-2 function in apical membrane trafficking involves aspects independent of the syntaxin 3 interaction. ..
  13. Wiederkehr A, De Craene J, Ferro Novick S, Novick P. Functional specialization within a vesicle tethering complex: bypass of a subset of exocyst deletion mutants by Sec1p or Sec4p. J Cell Biol. 2004;167:875-87 pubmed
    ..Furthermore, a fraction of Sec1p can be coprecipitated with the exoycst. Our results suggest that Sec1p couples exocyst-mediated vesicle tethering with SNARE-mediated docking and fusion. ..
  14. Nichols B, Holthuis J, Pelham H. The Sec1p homologue Vps45p binds to the syntaxin Tlg2p. Eur J Cell Biol. 1998;77:263-8 pubmed
    ..It appears that the role of Vps45p in protein traffic is more complex than has previously been assumed...
  15. Gil Pisa I, Munarriz Cuezva E, Ramos Miguel A, Urigüen L, Meana J, Garcia Sevilla J. Regulation of munc18-1 and syntaxin-1A interactive partners in schizophrenia prefrontal cortex: down-regulation of munc18-1a isoform and 75 kDa SNARE complex after antipsychotic treatment. Int J Neuropsychopharmacol. 2012;15:573-88 pubmed publisher
    ..Moreover, antipsychotic drug treatment is associated with lower content of key proteins of the exocytotic machinery, which could result in a destabilization/impairment of neurosecretion. ..
  16. Zilly F, Sørensen J, Jahn R, Lang T. Munc18-bound syntaxin readily forms SNARE complexes with synaptobrevin in native plasma membranes. PLoS Biol. 2006;4:e330 pubmed
    ..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. ..
  17. Riento K, Jantti J, Jansson S, Hielm S, Lehtonen E, Ehnholm C, et al. A sec1-related vesicle-transport protein that is expressed predominantly in epithelial cells. Eur J Biochem. 1996;239:638-46 pubmed
  18. Craig T, Evans G, Morgan A. Physiological regulation of Munc18/nSec1 phosphorylation on serine-313. J Neurochem. 2003;86:1450-7 pubmed
    ..Furthermore, such changes in release kinetics are associated with long-term potentiation and depression, thus implicating nSec1 phosphorylation as a potential regulatory mechanism underlying presynaptic plasticity. ..
  19. Zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet. 2009;85:482-92 pubmed publisher
    ..Activity of natural killer and cytotoxic T cells was markedly reduced or absent, as determined by CD107 degranulation. Our findings thus identify a key role for STXBP2 in lytic granule exocytosis. ..
  20. Rizo J, Rosenmund C. Synaptic vesicle fusion. Nat Struct Mol Biol. 2008;15:665-74 pubmed
    ..Elucidation of the release mechanism will require a full understanding of the network of interactions among all these proteins and the membranes. ..
  21. Carr C, Rizo J. At the junction of SNARE and SM protein function. Curr Opin Cell Biol. 2010;22:488-95 pubmed publisher
    ..The available data suggest sequential models that describe how the soluble SM protein might first regulate SNARE complex assembly and then cooperate with SNAREs to stimulate membrane fusion. ..
  22. Kanda H, Tamori Y, Shinoda H, Yoshikawa M, Sakaue M, Udagawa J, et al. Adipocytes from Munc18c-null mice show increased sensitivity to insulin-stimulated GLUT4 externalization. J Clin Invest. 2005;115:291-301 pubmed
  23. Swanson D, Steel J, Valle D. Identification and characterization of the human ortholog of rat STXBP1, a protein implicated in vesicle trafficking and neurotransmitter release. Genomics. 1998;48:373-6 pubmed
    ..However, due to its evolutionary conservation and abundant expression in retina and brain, STXBP1 should be considered a candidate gene for retinal and/or neural disorders mapping to 9q34.1. ..
  24. Umahara M, Okada S, Yamada E, Saito T, Ohshima K, Hashimoto K, et al. Tyrosine phosphorylation of Munc18c regulates platelet-derived growth factor-stimulated glucose transporter 4 translocation in 3T3L1 adipocytes. Endocrinology. 2008;149:40-9 pubmed
    ..Together, these data demonstrate that one mechanism accounting for the PDGF induction of Glut4 translocation is the suppression of the Munc18c negative regulation of Syntaxin 4 function. ..
  25. Pertsinidis A, Mukherjee K, Sharma M, Pang Z, Park S, Zhang Y, et al. Ultrahigh-resolution imaging reveals formation of neuronal SNARE/Munc18 complexes in situ. Proc Natl Acad Sci U S A. 2013;110:E2812-20 pubmed publisher
    ..Our superresolution imaging method provides a framework for investigating interactions between the synaptic vesicle fusion machinery and other subcellular systems in situ. ..
  26. Shen J, Tareste D, Paumet F, Rothman J, Melia T. Selective activation of cognate SNAREpins by Sec1/Munc18 proteins. Cell. 2007;128:183-95 pubmed
    ..Munc18-1 accelerates fusion only for the cognate SNAREs for exocytosis, therefore enhancing fusion specificity. ..
  27. Toonen R, Kochubey O, de Wit H, Gulyas Kovacs A, Konijnenburg B, Sørensen J, et al. Dissecting docking and tethering of secretory vesicles at the target membrane. EMBO J. 2006;25:3725-37 pubmed
    ..We conclude that docking vesicles either undock immediately or are captured by minimal tethering machinery and converted in a munc18-1/syntaxin-dependent, strongly tethered, fusion-competent state. ..
  28. Neiman A. Prospore membrane formation defines a developmentally regulated branch of the secretory pathway in yeast. J Cell Biol. 1998;140:29-37 pubmed
    ..Spore formation in yeast may be a useful model for understanding secretion-driven cell division events in a variety of plant and animal systems. ..
  29. Grote E, Carr C, Novick P. Ordering the final events in yeast exocytosis. J Cell Biol. 2000;151:439-52 pubmed
    ..In the sec18-1 mutant, cis-SNARE complexes containing surface-accessible Sncp accumulate in the plasma membrane. Thus, one function of Sec18p is to disassemble SNARE complexes on the postfusion membrane. ..
  30. Li Y, Gallwitz D, Peng R. Structure-based functional analysis reveals a role for the SM protein Sly1p in retrograde transport to the endoplasmic reticulum. Mol Biol Cell. 2005;16:3951-62 pubmed
    ..Together, these results indicate a previously unrecognized function of Sly1p in retrograde transport to the endoplasmic reticulum. ..
  31. Weber Boyvat M, Aro N, Chernov K, Nyman T, Jantti J. Sec1p and Mso1p C-terminal tails cooperate with the SNAREs and Sec4p in polarized exocytosis. Mol Biol Cell. 2011;22:230-44 pubmed publisher
    ..This association depends on the Sec4p guanine nucleotide exchange factor Sec2p. Our results reveal a novel binding mode between the Sec1p C-terminal tail and the SNARE complex, and suggest a role for Mso1p as an effector of Sec4p. ..
  32. Tareste D, Shen J, Melia T, Rothman J. SNAREpin/Munc18 promotes adhesion and fusion of large vesicles to giant membranes. Proc Natl Acad Sci U S A. 2008;105:2380-5 pubmed publisher
    ..We expect that the study of SNARE-mediated fusion with giant membranes will find wide applicability in distinguishing adhesion- and fusion-directed SNARE regulatory factors. ..
  33. Saitsu H, Kato M, Mizuguchi T, Hamada K, Osaka H, Tohyama J, et al. De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet. 2008;40:782-8 pubmed publisher
    ..Furthermore, binding of the mutant protein to syntaxin was impaired. These findings suggest that haploinsufficiency of STXBP1 causes EIEE. ..
  34. Han G, Malintan N, Collins B, Meunier F, Sugita S. Munc18-1 as a key regulator of neurosecretion. J Neurochem. 2010;115:1-10 pubmed publisher
    ..In this review, we summarize these recent advances and attempt to propose an updated model of the pleiotropic functions of Munc18-1 in neuroexocytosis. ..
  35. Lupashin V, Waters M. t-SNARE activation through transient interaction with a rab-like guanosine triphosphatase. Science. 1997;276:1255-8 pubmed
    ..The data suggest that the Rab protein Ypt1p transiently interacts with the t-SNARE Sed5p and results in displacement of the negative regulator Sly1p, allowing subsequent formation of the v-SNARE-t-SNARE targeting complex. ..
  36. Williams A, Ehm S, Jacobson N, Xu D, Hay J. rsly1 binding to syntaxin 5 is required for endoplasmic reticulum-to-Golgi transport but does not promote SNARE motif accessibility. Mol Biol Cell. 2004;15:162-75 pubmed
    ..Our results argue that although rsly1 does not seem to regulate the availability of syntaxin 5, its function is intimately associated with syntaxin binding, perhaps promoting a later step in SNARE complex formation or function. ..
  37. Torres J, Funk H, Zegers M, ter Beest M. The syntaxin 4 N terminus regulates its basolateral targeting by munc18c-dependent and -independent mechanisms. J Biol Chem. 2011;286:10834-46 pubmed publisher
    ..First, it harbors the sorting motif, which targets syntaxin 4 basolaterally in a munc18c-independent manner and second, it allows for munc18c binding, which stabilizes the protein in a munc18c-dependent manner. ..
  38. Peng R, Guetg C, Abellan E, Fussenegger M. Munc18b regulates core SNARE complex assembly and constitutive exocytosis by interacting with the N-peptide and the closed-conformation C-terminus of syntaxin 3. Biochem J. 2010;431:353-61 pubmed publisher
  39. Jewell J, Oh E, Thurmond D. Exocytosis mechanisms underlying insulin release and glucose uptake: conserved roles for Munc18c and syntaxin 4. Am J Physiol Regul Integr Comp Physiol. 2010;298:R517-31 pubmed publisher
    ..Thus, we provide here an up-to-date historical review of advancements in defining the roles and molecular mechanisms of Munc18-syntaxin complexes in the pathophysiology of Type 2 diabetes. ..
  40. Fu J, Naren A, Gao X, Ahmmed G, Malik A. Protease-activated receptor-1 activation of endothelial cells induces protein kinase Calpha-dependent phosphorylation of syntaxin 4 and Munc18c: role in signaling p-selectin expression. J Biol Chem. 2005;280:3178-84 pubmed
  41. Tomas A, Meda P, Regazzi R, Pessin J, Halban P. Munc 18-1 and granuphilin collaborate during insulin granule exocytosis. Traffic. 2008;9:813-32 pubmed publisher
  42. Aalto M, Ronne H, Keranen S. Yeast syntaxins Sso1p and Sso2p belong to a family of related membrane proteins that function in vesicular transport. EMBO J. 1993;12:4095-104 pubmed
    ..A nematode cDNA product also belongs to the new protein family. The new protein family is thus present in a wide variety of eukaryotic cells, where its members function at different stages in vesicular transport. ..
  43. Rickman C, Medine C, Bergmann A, Duncan R. Functionally and spatially distinct modes of munc18-syntaxin 1 interaction. J Biol Chem. 2007;282:12097-103 pubmed
    ..Furthermore, these functionally divergent interactions occur at distinct cellular locations. These findings provide a molecular explanation for the multiple, spatially distinct roles of munc18-1. ..
  44. Malintan N, Nguyen T, Han L, Latham C, Osborne S, Wen P, et al. Abrogating Munc18-1-SNARE complex interaction has limited impact on exocytosis in PC12 cells. J Biol Chem. 2009;284:21637-46 pubmed publisher
    ..The Munc18-1 hydrophobic pocket is therefore critical for SNARE complex binding. However, mutations abrogating this interaction have a limited impact on Ca(2+)-dependent exocytosis in PC12 cells. ..
  45. Burgoyne R, Barclay J, Ciufo L, Graham M, Handley M, Morgan A. The functions of Munc18-1 in regulated exocytosis. Ann N Y Acad Sci. 2009;1152:76-86 pubmed publisher
  46. Rickman C, Davletov B. Arachidonic acid allows SNARE complex formation in the presence of Munc18. Chem Biol. 2005;12:545-53 pubmed
  47. Shi L, Kümmel D, Coleman J, Melia T, Giraudo C. Dual roles of Munc18-1 rely on distinct binding modes of the central cavity with Stx1A and SNARE complex. Mol Biol Cell. 2011;22:4150-60 pubmed publisher
    Sec1/Munc18 proteins play a fundamental role in multiple steps of intracellular membrane trafficking...
  48. Schraw T, Lemons P, Dean W, Whiteheart S. A role for Sec1/Munc18 proteins in platelet exocytosis. Biochem J. 2003;374:207-17 pubmed publisher
    ..Three Sec1/Munc18 proteins (SM proteins) are present in platelets (Munc18a, Munc18b and Munc18c) and they bind to and potentially ..
  49. Mastrangelo M, Peron A, Spaccini L, Novara F, Scelsa B, Introvini P, et al. Neonatal suppression-burst without epileptic seizures: expanding the electroclinical phenotype of STXBP1-related, early-onset encephalopathy. Epileptic Disord. 2013;15:55-61 pubmed publisher
    ..Our findings suggest that molecular analysis of STXBP1 should be considered for newborns affected by neonatal encephalopathy associated with a peculiar EEG pattern, even in the absence of neonatal epileptic seizures. ..
  50. Xu Y, Su L, Rizo J. Binding of Munc18-1 to synaptobrevin and to the SNARE four-helix bundle. Biochemistry. 2010;49:1568-76 pubmed publisher
  51. Barclay J, Craig T, Fisher R, Ciufo L, Evans G, Morgan A, et al. Phosphorylation of Munc18 by protein kinase C regulates the kinetics of exocytosis. J Biol Chem. 2003;278:10538-45 pubmed
    ..Phosphorylation of Munc18 by PKC may provide a mechanism for the control of exocytosis and thereby synaptic plasticity. ..
  52. Peng R, Gallwitz D. Multiple SNARE interactions of an SM protein: Sed5p/Sly1p binding is dispensable for transport. EMBO J. 2004;23:3939-49 pubmed
    ..The newly identified, direct interactions of the SM protein with nonsytaxin SNAREs might provide a molecular mechanism by which SNAREs can be activated to engage in pairing and assemble into fusogenic SNARE complexes. ..
  53. Dong Y, Wan Q, Yang X, Bai L, Xu P. Interaction of Munc18 and Syntaxin in the regulation of insulin secretion. Biochem Biophys Res Commun. 2007;360:609-14 pubmed
    ..We propose that Munc18-1 inhibitis the SNARE complex assembly by stabilizing Syntaxin1A in a closed conformation in vesicle priming process, therefore negatively regulates insulin secretion. ..