Munc-18

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:

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 6
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See also

References
  1. 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.
  2. Brenner, S. (May 1974). "The Genetics of Caenorhabditis Elegans". Genetics. 77 (1): 71–94. PMC 1213120. PMID 4366476.
  3. 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. PMC 1570500. PMID 17002520.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. "Archived copy". Archived from the original on 2009-08-18. Retrieved 2010-02-05.CS1 maint: archived copy as title (link)
  10. 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.
  11. 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.
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