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.
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
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. PMID1347782. S2CID30965606.
↑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. PMID23073634.
↑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. PMID15935055. S2CID24920185.
↑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. PMID23057743.