Munc-18

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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]

Contents

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
symbolname
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

Related Research Articles

<span class="mw-page-title-main">Synaptic vesicle</span> Neurotransmitters that are released at the synapse

In a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell. The area in the axon that holds groups of vesicles is an axon terminal or "terminal bouton". Up to 130 vesicles can be released per bouton over a ten-minute period of stimulation at 0.2 Hz. In the visual cortex of the human brain, synaptic vesicles have an average diameter of 39.5 nanometers (nm) with a standard deviation of 5.1 nm.

<span class="mw-page-title-main">SNARE protein</span> Protein family

SNARE proteins – "SNAPREceptors" – are a large protein family consisting of at least 24 members in yeasts, more than 60 members in mammalian cells, and some numbers in plants. The primary role of SNARE proteins is to mediate the fusion of vesicles with the target membrane; this notably mediates exocytosis, but can also mediate the fusion of vesicles with membrane-bound compartments. The best studied SNAREs are those that mediate the release of synaptic vesicles containing neurotransmitters in neurons. These neuronal SNAREs are the targets of the neurotoxins responsible for botulism and tetanus produced by certain bacteria.

<span class="mw-page-title-main">SNAP25</span> Protein-coding gene in the species Homo sapiens

Synaptosomal-Associated Protein, 25kDa (SNAP-25) is a Target Soluble NSF (N-ethylmaleimide-sensitive factor) Attachment Protein Receptor (t-SNARE) protein encoded by the SNAP25 gene found on chromosome 20p12.2 in humans. SNAP-25 is a component of the trans-SNARE complex, which accounts for membrane fusion specificity and directly executes fusion by forming a tight complex that brings the synaptic vesicle and plasma membranes together.

<span class="mw-page-title-main">Complexin</span>

Complexin (also known as synaphin) refers to a one of a small set of eukaryotic cytoplasmic neuronal proteins which binds to the SNARE protein complex (SNAREpin) with a high affinity. These are called synaphin 1 and 2. In the presence of Ca2+, the transport vesicle protein synaptotagmin displaces complexin, allowing the SNARE protein complex to bind the transport vesicle to the presynaptic membrane.

<span class="mw-page-title-main">STX1A</span> Protein-coding gene in the species Homo sapiens

Syntaxin-1A is a protein that in humans is encoded by the STX1A gene.

<span class="mw-page-title-main">SNAP23</span> Protein-coding gene in the species Homo sapiens

Synaptosomal-associated protein 23 is a protein that in humans is encoded by the SNAP23 gene. Two alternative transcript variants encoding different protein isoforms have been described for this gene.

<span class="mw-page-title-main">STX4</span> Protein-coding gene in the species Homo sapiens

Syntaxin-4 is a protein that in humans is encoded by the STX4 gene.

<span class="mw-page-title-main">VAMP2</span> Protein-coding gene in the species Homo sapiens

Vesicle-associated membrane protein 2 (VAMP2) is a protein that in humans is encoded by the VAMP2 gene.

<span class="mw-page-title-main">STXBP1</span> Protein-coding gene in the species Homo sapiens

Syntaxin-binding protein 1 is a protein that in humans is encoded by the STXBP1 gene. This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with neurological disorders including epilepsy, intellectual disability, and movement disorders.

<span class="mw-page-title-main">NAPA (gene)</span> Protein-coding gene in the species Homo sapiens

N-ethylmaleimide-sensitive factor Attachment Protein Alpha, also known as SNAP-α, is a SNAP protein that is involved in the intra-cellular trafficking and fusing of vesicles to target membranes in cells.

<span class="mw-page-title-main">VAMP3</span> Protein-coding gene in the species Homo sapiens

Vesicle-associated membrane protein 3 is a protein that in humans is encoded by the VAMP3 gene.

<span class="mw-page-title-main">STX2</span> Protein-coding gene in the species Homo sapiens

Syntaxin-2, also known as epimorphin, is a protein that in humans is encoded by the STX2 gene.

<span class="mw-page-title-main">Vesicle-associated membrane protein 8</span> Protein-coding gene in the species Homo sapiens

Vesicle-associated membrane protein 8 is a protein that in humans is encoded by the VAMP8 gene.

<span class="mw-page-title-main">Syntaxin binding protein 2</span> Protein-coding gene in the species Homo sapiens

Syntaxin-binding protein 2 is a protein that in humans is encoded by the STXBP2 gene.

<span class="mw-page-title-main">CPLX1</span> Protein-coding gene in the species Homo sapiens

Complexin-1 is a protein that in humans is encoded by the CPLX1 gene.

<span class="mw-page-title-main">VAMP1</span> Protein-coding gene in the species Homo sapiens

Vesicle-associated membrane protein 1 (VAMP1) is a protein that in humans is encoded by the VAMP1 gene.

<span class="mw-page-title-main">STXBP5</span> Protein-coding gene in the species Homo sapiens

Syntaxin-binding protein 5 is a protein that in humans is encoded by the STXBP5 gene. It is also known as tomosyn, after 友, "friend" in Japanese, for its role as a binding protein.

<span class="mw-page-title-main">Syntaxin 3</span> Protein-coding gene in the species Homo sapiens

Syntaxin 3, also known as STX3, is a protein which in humans is encoded by the STX3 gene.

<span class="mw-page-title-main">Syntaxin</span> Group of proteins

Syntaxins are a family of membrane integrated Q-SNARE proteins participating in exocytosis.

Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. In the latter case, it is the end stage of secretion from secretory vesicles, where their contents are expelled from the cell through exocytosis. Vesicles can also fuse with other target cell compartments, such as a lysosome. Exocytosis occurs when secretory vesicles transiently dock and fuse at the base of cup-shaped structures at the cell plasma membrane called porosome, the universal secretory machinery in cells. Vesicle fusion may depend on SNARE proteins in the presence of increased intracellular calcium (Ca2+) concentration.

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. S2CID   30965606.
  2. ↑ Brenner, S. (May 1974). "The Genetics of Caenorhabditis Elegans". Genetics. 77 (1): 71–94. doi:10.1093/genetics/77.1.71. 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. S2CID   46713725.
  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. S2CID   30026611.
  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. S2CID   24920185.
  9. ↑ "Members :: Network of European Neuroscience Institutes". Archived from the original on 2009-08-18. Retrieved 2010-02-05.
  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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