Munc-18 (an acronym for mammalian uncoordinated-18) proteins are the mammalian homologue of UNC-18 (which was first discovered in the nematode worm C. elegans[1][2]) and are a member of the Sec1/Munc18-like (SM) protein family. Munc-18 proteins have been identified as essential components of the synaptic vesicle fusion protein complex and are crucial for the regulated exocytosis of neurons and neuroendocrine cells.[3]
Munc-18 binds syntaxin and forms a syntaxin/munc-18 complex which is thought to precede and/or regulate vesicle priming, a process mediated by VAMP, SNAP-25 and syntaxin.[4] Munc18-1, a member of the SM family, has multiple roles in exocytosis.[5] It directly promotes syntaxin stability and either controls the spatially correct assembly of core complexes for SNARE-dependent fusion, or acts as a direct component of the fusion machinery through the interaction with SNARE core.[6] Munc18a, which binds specifically to the N-terminal of syntaxin, causes a conformation change, activating syntaxin, which in turn connects to the ternary-SNARE complex.[7] Deletion of munc18-1 leads to a defect in secretory vesicle docking.[8] Furthermore, the munc18-1 deficient mouse is the first mouse model wherein neurotransmitter secretion is completely absent. This mouse model is appropriately titled the "silent mouse."[9]
Mechanismedit
This outline below presents a broad modeling of how Munc-18 is thought to play a role in vesicle docking and fusion, allowing for intentional exocytosis.[10] As it is a combined preliminary modeling, more research is necessary to fully understand the role of Munc-18 in this process.
Munc18-1 binds to a closed form of syntaxin-1, blocking SNARE complex formation. This is thought to affect vesicle docking
Munc13 opens syntaxin-1, Munc18-1 is translocated to the SNARE complex, which releases the inhibitory effect, allowing assembly (specifically of the alpha helix 4 part bundle)
It is thought that Munc18-1 stabilizes the formed trans-SNARE complex, preventing its dissociation
The SNARE complex, potentially with the assistance of Munc-18 brings the membranes together and causes fusion
It has also been shown in one study that Munc-18 binds to the C-terminus of synaptobrevin, suggesting that this protein plays an important role in membrane fusion.[11]
Family membersedit
The following is a list of human munc-18 proteins:
^Hosono R (1992). "The unc-18 Gene Encodes a Novel Protein Affecting the Kinetics of Acetylcholine Metabolism in the Nematode Caenorhabditis elegans". Journal of Neurochemistry. 58 (4): 1517–1525. doi:10.1111/j.1471-4159.1992.tb11373.x. PMID 1347782. S2CID 30965606.
^Brenner, S. (May 1974). "The Genetics of Caenorhabditis Elegans". Genetics. 77 (1): 71–94. doi:10.1093/genetics/77.1.71. PMC1213120. PMID 4366476.
^Zilly FE, Sørensen JB, Jahn R, Lang T (October 2006). "Munc18-bound syntaxin readily forms SNARE complexes with synaptobrevin in native plasma membranes". PLOS Biol. 4 (10): e330. doi:10.1371/journal.pbio.0040330. PMC1570500. PMID 17002520.
^Pevsner J, Hsu SC, Braun JE, Calakos N, Ting AE, Bennett MK, Scheller RH (August 1994). "Specificity and regulation of a synaptic vesicle docking complex". Neuron. 13 (2): 353–61. doi:10.1016/0896-6273(94)90352-2. PMID 8060616. S2CID 46713725.
^Burgoyne RD, Barclay JW, Ciufo LF, Graham ME, Handley MT, Morgan A (2009). "The functions of Munc18-1 in regulated exocytosis". Ann N Y Acad Sci. 1152 (1): 76–86. Bibcode:2009NYASA1152...76B. doi:10.1111/j.1749-6632.2008.03987.x. PMID 19161378. S2CID 30026611.
^Diao J, Su Z, Lu X, Yoon TY, Shin YK, Ha T (March 2010). "Single-Vesicle Fusion Assay Reveals Munc18-1 Binding to the SNARE Core Is Sufficient for Stimulating Membrane Fusion". ACS Chem Neurosci. 1 (3): 168–174. doi:10.1021/cn900034p. PMC2841011. PMID 20300453.
^Kasai, H.; Takahashi, N.; Tokumaru, H. (2012). "Distinct Initial SNARE Configurations Underlying the Diversity of Exocytosis". Physiological Reviews. 92 (4): 1915–1964. doi:10.1152/physrev.00007.2012. PMID 23073634.
^Toonen RF, de Vries KJ, Zalm R, Südhof TC, Verhage M (June 2005). "Munc18-1 stabilizes syntaxin 1, but is not essential for syntaxin 1 targeting and SNARE complex formation". J. Neurochem. 93 (6): 1393–400. doi:10.1111/j.1471-4159.2005.03128.x. PMID 15935055. S2CID 24920185.
^. Archived from the original on 2009-08-18. Retrieved 2010-02-05.
^Rizo, J.; Südhof, T. C. (2012). "The Membrane Fusion Enigma: SNAREs, Sec1/Munc18 Proteins, and Their Accomplices—Guilty as Charged?". Annual Review of Cell and Developmental Biology. 28: 279–308. doi:10.1146/annurev-cellbio-101011-155818. PMID 23057743.
^Xu, Y; Su, L; Rizo, J (2 March 2010). "Binding of Munc18-1 to synaptobrevin and to the SNARE four-helix bundle". Biochemistry. 49 (8): 1568–76. doi:10.1021/bi9021878. PMC2834481. PMID 20102228.
munc, acronym, mammalian, uncoordinated, proteins, mammalian, homologue, which, first, discovered, nematode, worm, elegans, member, sec1, munc18, like, protein, family, proteins, have, been, identified, essential, components, synaptic, vesicle, fusion, protein. Munc 18 an acronym for mammalian uncoordinated 18 proteins are the mammalian homologue of UNC 18 which was first discovered in the nematode worm C elegans 1 2 and are a member of the Sec1 Munc18 like SM protein family Munc 18 proteins have been identified as essential components of the synaptic vesicle fusion protein complex and are crucial for the regulated exocytosis of neurons and neuroendocrine cells 3 Contents 1 Function 1 1 Mechanism 2 Family members 3 See also 4 References 5 External linksFunction editMunc 18 binds syntaxin and forms a syntaxin munc 18 complex which is thought to precede and or regulate vesicle priming a process mediated by VAMP SNAP 25 and syntaxin 4 Munc18 1 a member of the SM family has multiple roles in exocytosis 5 It directly promotes syntaxin stability and either controls the spatially correct assembly of core complexes for SNARE dependent fusion or acts as a direct component of the fusion machinery through the interaction with SNARE core 6 Munc18a which binds specifically to the N terminal of syntaxin causes a conformation change activating syntaxin which in turn connects to the ternary SNARE complex 7 Deletion of munc18 1 leads to a defect in secretory vesicle docking 8 Furthermore the munc18 1 deficient mouse is the first mouse model wherein neurotransmitter secretion is completely absent This mouse model is appropriately titled the silent mouse 9 Mechanism edit This outline below presents a broad modeling of how Munc 18 is thought to play a role in vesicle docking and fusion allowing for intentional exocytosis 10 As it is a combined preliminary modeling more research is necessary to fully understand the role of Munc 18 in this process Munc18 1 binds to a closed form of syntaxin 1 blocking SNARE complex formation This is thought to affect vesicle docking Munc13 opens syntaxin 1 Munc18 1 is translocated to the SNARE complex which releases the inhibitory effect allowing assembly specifically of the alpha helix 4 part bundle It is thought that Munc18 1 stabilizes the formed trans SNARE complex preventing its dissociation The SNARE complex potentially with the assistance of Munc 18 brings the membranes together and causes fusion It has also been shown in one study that Munc 18 binds to the C terminus of synaptobrevin suggesting that this protein plays an important role in membrane fusion 11 Family members editThe following is a list of human munc 18 proteins protein gene symbol name MUNC18 1 STXBP1 syntaxin binding protein 1 MUNC18 2 STXBP2 syntaxin binding protein 2 MUNC18 3 STXBP3 syntaxin binding protein 3 MUNC18 4 STXBP4 syntaxin binding protein 4 MUNC18 5 STXBP5 syntaxin binding protein 5 MUNC18 6 STXBP6 syntaxin binding protein 6See also editVesicle fusion Exocytosis Syntaxin SNAREReferences edit Hosono R 1992 The unc 18 Gene Encodes a Novel Protein Affecting the Kinetics of Acetylcholine Metabolism in the Nematode Caenorhabditis elegans Journal of Neurochemistry 58 4 1517 1525 doi 10 1111 j 1471 4159 1992 tb11373 x PMID 1347782 S2CID 30965606 Brenner S May 1974 The Genetics of Caenorhabditis Elegans Genetics 77 1 71 94 doi 10 1093 genetics 77 1 71 PMC 1213120 PMID 4366476 Zilly FE Sorensen JB Jahn R Lang T October 2006 Munc18 bound syntaxin readily forms SNARE complexes with synaptobrevin in native plasma membranes PLOS Biol 4 10 e330 doi 10 1371 journal pbio 0040330 PMC 1570500 PMID 17002520 Pevsner J Hsu SC Braun JE Calakos N Ting AE Bennett MK Scheller RH August 1994 Specificity and regulation of a synaptic vesicle docking complex Neuron 13 2 353 61 doi 10 1016 0896 6273 94 90352 2 PMID 8060616 S2CID 46713725 Burgoyne RD Barclay JW Ciufo LF Graham ME Handley MT Morgan A 2009 The functions of Munc18 1 in regulated exocytosis Ann N Y Acad Sci 1152 1 76 86 Bibcode 2009NYASA1152 76B doi 10 1111 j 1749 6632 2008 03987 x PMID 19161378 S2CID 30026611 Diao J Su Z Lu X Yoon TY Shin YK Ha T March 2010 Single Vesicle Fusion Assay Reveals Munc18 1 Binding to the SNARE Core Is Sufficient for Stimulating Membrane Fusion ACS Chem Neurosci 1 3 168 174 doi 10 1021 cn900034p PMC 2841011 PMID 20300453 Kasai H Takahashi N Tokumaru H 2012 Distinct Initial SNARE Configurations Underlying the Diversity of Exocytosis Physiological Reviews 92 4 1915 1964 doi 10 1152 physrev 00007 2012 PMID 23073634 Toonen RF de Vries KJ Zalm R Sudhof TC Verhage M June 2005 Munc18 1 stabilizes syntaxin 1 but is not essential for syntaxin 1 targeting and SNARE complex formation J Neurochem 93 6 1393 400 doi 10 1111 j 1471 4159 2005 03128 x PMID 15935055 S2CID 24920185 Members Network of European Neuroscience Institutes Archived from the original on 2009 08 18 Retrieved 2010 02 05 Rizo J Sudhof T C 2012 The Membrane Fusion Enigma SNAREs Sec1 Munc18 Proteins and Their Accomplices Guilty as Charged Annual Review of Cell and Developmental Biology 28 279 308 doi 10 1146 annurev cellbio 101011 155818 PMID 23057743 Xu Y Su L Rizo J 2 March 2010 Binding of Munc18 1 to synaptobrevin and to the SNARE four helix bundle Biochemistry 49 8 1568 76 doi 10 1021 bi9021878 PMC 2834481 PMID 20102228 External links editMunc18 Proteins at the U S National Library of Medicine Medical Subject Headings MeSH Retrieved from https en wikipedia org w index php title Munc 18 amp oldid 1188036556, wikipedia, wiki, book, books, library,
