'''Munc-18''' (an acronym for '''m'''ammalian '''unc'''oordinated'''-18''') proteins are the mammalian homologue of UNC-18 (which was first discovered in the nematode worm C. elegans<ref>{{cite journal|doi=10.1111/j.1471-4159.1992.tb11373.x | volume=58 | title=The unc-18 Gene Encodes a Novel Protein Affecting the Kinetics of Acetylcholine Metabolism in the Nematode Caenorhabditis elegans | journal=Journal of Neurochemistry | pages=1517–1525 | vauthors=Hosono R| year=1992 | issue=4 | pmid=1347782 | s2cid=30965606 }}</ref><ref>{{Cite journal | url=http://www.genetics.org/content/77/1/71.long |title = The Genetics of Caenorhabditis Elegans|journal = Genetics|date = May 1974|volume = 77|issue = 1|pages = 71–94|last1 = Brenner|first1 = S.| doi=10.1093/genetics/77.1.71 |pmid = 4366476|pmc = 1213120}}</ref>) 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.<ref name="pmid17002520">{{cite journal |vauthors=Zilly FE, Sørensen JB, Jahn R, Lang T | title = Munc18-bound syntaxin readily forms SNARE complexes with synaptobrevin in native plasma membranes | journal = PLOS Biol. | volume = 4 | issue = 10 | pages = e330 |date=October 2006 | pmid = 17002520 | pmc = 1570500 | doi = 10.1371/journal.pbio.0040330 | doi-access = free }}</ref>
==Function== 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.<ref name="pmid8060616">{{cite journal |vauthors=Pevsner J, Hsu SC, Braun JE, Calakos N, Ting AE, Bennett MK, Scheller RH | title = Specificity and regulation of a synaptic vesicle docking complex | journal = Neuron | volume = 13 | issue = 2 | pages = 353–61 |date=August 1994 | pmid = 8060616 | doi = 10.1016/0896-6273(94)90352-2| s2cid = 46713725 | doi-access = free }}</ref> Munc18-1, a member of the SM family, has multiple roles in exocytosis.<ref name="pmid 19161378">{{cite journal |vauthors=Burgoyne RD, Barclay JW, Ciufo LF, Graham ME, Handley MT, Morgan A |title= The functions of Munc18-1 in regulated exocytosis. |journal= Ann N Y Acad Sci |volume=1152 |pages= 76–86 |year= 2009 |issue= 1 |pmid= 19161378 |doi=10.1111/j.1749-6632.2008.03987.x|bibcode= 2009NYASA1152...76B |s2cid= 30026611 }}</ref> 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.<ref name="pmid20300453">{{cite journal |vauthors=Diao J, Su Z, Lu X, Yoon TY, Shin YK, Ha T | title = Single-Vesicle Fusion Assay Reveals Munc18-1 Binding to the SNARE Core Is Sufficient for Stimulating Membrane Fusion. | journal = ACS Chem Neurosci | volume = 1 | issue = 3 | pages = 168–174 |date=March 2010 | pmid = 20300453 | doi = 10.1021/cn900034p | pmc=2841011}}</ref> 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.<ref>{{Cite journal | last1 = Kasai | first1 = H. | last2 = Takahashi | first2 = N. | last3 = Tokumaru | first3 = H. | doi = 10.1152/physrev.00007.2012 | title = Distinct Initial SNARE Configurations Underlying the Diversity of Exocytosis | journal = Physiological Reviews | volume = 92 | issue = 4 | pages = 1915–1964 | year = 2012 | pmid = 23073634 }}</ref> Deletion of munc18-1 leads to a defect in secretory vesicle docking.<ref name="pmid15935055">{{cite journal |vauthors=Toonen RF, de Vries KJ, Zalm R, Südhof TC, Verhage M | title = Munc18-1 stabilizes syntaxin 1, but is not essential for syntaxin 1 targeting and SNARE complex formation | journal = J. Neurochem. | volume = 93 | issue = 6 | pages = 1393–400 |date=June 2005 | pmid = 15935055 | doi = 10.1111/j.1471-4159.2005.03128.x | s2cid = 24920185 }}</ref> 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."<ref>{{cite web |url=http://www.eni-net.org/organization/members/prof-matthijs-verhage/ |title=Members :: Network of European Neuroscience Institutes |accessdate=2010-02-05 |url-status=dead |archive-url=https://web.archive.org/web/20090818022540/http://www.eni-net.org/organization/members/prof-matthijs-verhage/ |archive-date=2009-08-18 }}</ref>
===Mechanism=== 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.<ref>{{Cite journal | last1 = Rizo | first1 = J. | last2 = Südhof | first2 = T. C. | doi = 10.1146/annurev-cellbio-101011-155818 | title = The Membrane Fusion Enigma: SNAREs, Sec1/Munc18 Proteins, and Their Accomplices—Guilty as Charged? | journal = Annual Review of Cell and Developmental Biology | volume = 28 | pages = 279–308 | year = 2012 | pmid = 23057743 }}</ref> 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.<ref>{{cite journal |last1=Xu |first1=Y |last2=Su |first2=L |last3=Rizo |first3=J |title=Binding of Munc18-1 to synaptobrevin and to the SNARE four-helix bundle. |journal=Biochemistry |date=2 March 2010 |volume=49 |issue=8 |pages=1568–76 |doi=10.1021/bi9021878 |pmid=20102228|pmc=2834481 }}</ref>
== Family members == The following is a list of human munc-18 proteins:
{| class="wikitable" border="1" |- ! rowspan = 2 | protein ! colspan = 2 | 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 6 |}
== See also == *Vesicle fusion *Exocytosis *Syntaxin *SNARE
== References == {{reflist}}
==External links== * {{MeshName|Munc18+Proteins}}
{{Vesicular transport proteins}}
Category:Neurophysiology Category:Human proteins