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词条 Munc-18
释义

  1. Function

     Mechanism 

  2. Family members

  3. See also

  4. References

  5. External links

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]

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.[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

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.

  1. Munc18-1 binds to a closed form of syntaxin-1, blocking SNARE complex formation. This is thought to affect vesicle docking
  2. 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)
  3. It is thought that Munc18-1 stabilizes the formed trans-SNARE complex, preventing its dissociation
  4. 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

The following is a list of human munc-18 proteins:

proteingene
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

1. ^{{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}}
2. ^http://www.genetics.org/content/77/1/71.long
3. ^{{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 | url = | issn = }}
4. ^{{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| url = | issn = }}
5. ^{{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 |pmid= 19161378 |doi=10.1111/j.1749-6632.2008.03987.x}}
6. ^{{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 | url = | issn = | pmc=2841011}}
7. ^{{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 | pmc = }}
8. ^{{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 | url = | issn = }}
9. ^{{cite web |url=http://www.eni-net.org/organization/members/prof-matthijs-verhage/ |title=Archived copy |accessdate=2010-02-05 |deadurl=yes |archiveurl=https://web.archive.org/web/20090818022540/http://www.eni-net.org/organization/members/prof-matthijs-verhage/ |archivedate=2009-08-18 |df= }}
10. ^{{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 | pmc = }}
11. ^{{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}}

External links

  • {{MeshName|Munc18+Proteins}}
{{Vesicular transport proteins}}

2 : Neurophysiology|Human proteins
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