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

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

See also

References

  1. ↑ http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.1992.tb11373.x/abstract
  2. ↑ http://www.genetics.org/content/77/1/71.long
  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. PMC 1570500 Freely accessible. PMID 17002520. doi:10.1371/journal.pbio.0040330.
  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. PMID 8060616. doi:10.1016/0896-6273(94)90352-2.
  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: 76–86. PMID 19161378. doi:10.1111/j.1749-6632.2008.03987.x.
  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. PMC 2841011 Freely accessible. PMID 20300453. doi:10.1021/cn900034p.
  7. ↑ Kasai, H.; Takahashi, N.; Tokumaru, H. (2012). "Distinct Initial SNARE Configurations Underlying the Diversity of Exocytosis". Physiological Reviews. 92 (4): 1915–1964. PMID 23073634. doi:10.1152/physrev.00007.2012.
  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. PMID 15935055. doi:10.1111/j.1471-4159.2005.03128.x.
  9. ↑ http://www.eni-net.org/organization/members/prof-matthijs-verhage/
  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. PMID 23057743. doi:10.1146/annurev-cellbio-101011-155818.
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