STXBP1

STXBP1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 3PUJ
Identifiers
Aliases	STXBP1, MUNC18-1, NSEC1, P67, RBSEC1, UNC18, syntaxin binding protein 1
External IDs	OMIM: 602926; MGI: 107363; HomoloGene: 2382; GeneCards: STXBP1; OMA:STXBP1 - orthologs
Gene location (Human) Chr. Chromosome 9 (human)[1] Band 9q34.11 Start 127,579,370 bp[1] End 127,696,027 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2 B|2 22.09 cM Start 32,677,614 bp[2] End 32,737,257 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in middle temporal gyrus lateral nuclear group of thalamus Brodmann area 23 Pons superior frontal gyrus primary visual cortex right hemisphere of cerebellum pars compacta postcentral gyrus paraflocculus of cerebellum Top expressed in neural layer of retina pontine nuclei inferior colliculi perirhinal cortex superior colliculus central gray substance of midbrain piriform cortex Medulla Oblongata cerebellar cortex medial vestibular nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein domain specific binding protein N-terminus binding syntaxin-1 binding protein binding identical protein binding syntaxin binding protein kinase binding SNARE binding RNA binding phospholipase binding Cellular component platelet alpha granule membrane myelin sheath plasma membrane nucleoplasm terminal bouton mitochondrion extracellular exosome cytoplasm cytosol presynaptic active zone membrane nucleus cytoskeleton axon perinuclear region of cytoplasm presynapse postsynapse protein-containing complex phagocytic vesicle glutamatergic synapse Biological process negative regulation of neuron apoptotic process exocytosis axon target recognition protein stabilization platelet degranulation positive regulation of calcium ion-dependent exocytosis glutamate secretion regulation of synaptic vesicle fusion to presynaptic active zone membrane neuromuscular synaptic transmission negative regulation of synaptic transmission, GABAergic long-term depression protein transport positive regulation of exocytosis protein localization to plasma membrane platelet aggregation regulation of SNARE complex assembly synaptic vesicle maturation vesicle-mediated transport neurotransmitter secretion regulation of synaptic vesicle priming vesicle docking involved in exocytosis negative regulation of protein-containing complex assembly presynaptic dense core vesicle exocytosis developmental process involved in reproduction regulation of vesicle fusion response to estradiol positive regulation of mast cell degranulation positive regulation of vesicle docking positive regulation of glutamate secretion, neurotransmission transport synaptic vesicle priming cellular response to interferon-gamma SNARE complex assembly regulation of acrosomal vesicle exocytosis Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6812 20910 Ensembl ENSG00000136854 ENSMUSG00000026797 UniProt P61764 O08599 RefSeq (mRNA) NM_003165 NM_001032221 NM_001113569 NM_009295 RefSeq (protein) NP_001027392 NP_003156 NP_001361235 NP_001361236 NP_001361237 NP_001361238 NP_001361239 NP_001361240 NP_001361241 NP_001361242 NP_001361243 NP_001361244 NP_001107041 NP_033321 Location (UCSC) Chr 9: 127.58 – 127.7 Mb Chr 2: 32.68 – 32.74 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Syntaxin-binding protein 1 (also known as Munc18-1) is a protein that in humans is encoded by the STXBP1 gene.[5] 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.[6][7][8][9]

Structure

The STXBP1 gene is located on the q arm of chromosome 9 in position 34.11 and has 20 exons spanning 80,510 base pairs.[6] The encoded protein is a peripheral membrane protein located in the cytosol.[10][11] In the retina and cerebellum, an alternatively spliced transcript variant is expressed, containing an additional exon and totaling 603 amino acids.[5] Alternative splicing can produce an isoform with exon 19 and an isoform without.[12][13]

Function

The encoded protein may participate in the regulation of synaptic vesicle docking and fusion, possibly through interaction with GTP-binding proteins. It is essential for neurotransmission and binds syntaxin, a component of the synaptic vesicle fusion machinery probably in a 1:1 ratio. It can interact with syntaxins 1, 2, and 3 but not syntaxin 4 and may play a role in determining the specificity of intracellular fusion reactions.[10][11] This protein functions in a late stage of the intracellular membrane fusion process of exocytosis. Dissociation of this protein from syntaxin determines the kinetics of postfusion events.[14] This protein is essential for presynpatic vesicle release and is rapidly phosphorylated by protein kinase C upon neuronal depolarization.[15] The protein participates in the secretory pathway between the Golgi apparatus and cell membrane.[16][13]

Clinical significance

Epilepsy

Mutations in the STXBP1 cause early infantile epileptic encephalopathy type 4 (EIEE4), a severe form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases. Affected individuals have neonatal or infantile onset of seizures, profound intellectual disability, and MRI evidence of brain hypomyelination.[6][7] Inheritance of EIEE4 is autosomal dominant, but due to the severity of the condition most cases are de novo.[10][11]

This gene was initially discovered in 2008 as cause for this severe form of epilepsy also called Ohtahara syndrome. Since then it has become one of the most prominent genes for epileptic encephalopathies, and is increasingly being associated with other forms of epilepsy.[8][17]

Intellectual disability and movement disorders

STXBP1 variants are increasingly being identified in people with wider neurological problems, including intellectual disability or movement disorders without epilepsy.[8][9]

Expression

In melanocytic cells STXBP1 gene expression may be regulated by MITF.[18]

The STXBP1 gene is expressed in the brain and spinal cord and highly enriched in axons.[10][11] Expression of this protein is highest in the retina and cerebellum.[5][13]

Interactions

The encoded protein binds SYTL4.[10][11] STXBP1 has been shown to interact with STX2,[19][20] STX4[19][20] and STX1A.[20][21][22][23][24]

References

1. GRCh38: Ensembl release 89: ENSG00000136854 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000026797 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Swanson DA, Steel JM, Valle D (March 1998). "Identification and characterization of the human ortholog of rat STXBP1, a protein implicated in vesicle trafficking and neurotransmitter release". Genomics. 48 (3): 373–376. doi:10.1006/geno.1997.5202. PMID 9545644.
6. "Entrez Gene: STXBP1 syntaxin binding protein 1". Retrieved 2018-08-29. This article incorporates text from this source, which is in the public domain.
7. Stamberger H, Nikanorova M, Willemsen MH, Accorsi P, Angriman M, Baier H, et al. (March 2016). "STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy". Neurology. 86 (10): 954–962. doi:10.1212/WNL.0000000000002457. hdl:10067/1331590151162165141. PMID 26865513. S2CID 26206858.
8. Stamberger H, Crosiers D, Balagura G, Bonardi CM, Basu A, Cantalupo G, et al. (July 2022). "Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy Into Adulthood". Neurology. 99 (3): e221–e233. doi:10.1212/WNL.0000000000200715. PMC 9302932. PMID 35851549.
9. Spaull, R; Steel, D; Barwick, K; Prabhakar, P; Wakeling, E; Kurian, MA (2022-07-23). "STXBP1 Stop-Loss Mutation Associated with Complex Early Onset Movement Disorder without Epilepsy". Movement Disorders Clinical Practice. 9 (6): 837–840. doi:10.1002/mdc3.13509. hdl:1983/6fcc0c91-524a-4455-8291-61c09eea4332. ISSN 2330-1619. PMC 9346254. PMID 35937496.
10. "STXBP1 -Syntaxin-binding protein 1 - Homo sapiens (Human) - STXBP1 gene & protein". www.uniprot.org. Retrieved 2018-08-29. This article incorporates text available under the CC BY 4.0 license.
11. "UniProt: the universal protein knowledgebase". Nucleic Acids Research. 45 (D1): D158–D169. January 2017. doi:10.1093/nar/gkw1099. PMC 5210571. PMID 27899622.
12. Hamdan FF, Piton A, Gauthier J, Lortie A, Dubeau F, Dobrzeniecka S, et al. (June 2009). "De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy". Annals of Neurology. 65 (6): 748–753. doi:10.1002/ana.21625. PMID 19557857. S2CID 23892974.
13. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: {602926}: {04/22/2014}: . World Wide Web URL: https://omim.org/
14. Fisher RJ, Pevsner J, Burgoyne RD (February 2001). "Control of fusion pore dynamics during exocytosis by Munc18". Science. 291 (5505): 875–878. Bibcode:2001Sci...291..875F. doi:10.1126/science.291.5505.875. PMID 11157167. S2CID 27780447.
15. Wierda KD, Toonen RF, de Wit H, Brussaard AB, Verhage M (April 2007). "Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity". Neuron. 54 (2): 275–290. doi:10.1016/j.neuron.2007.04.001. PMID 17442248. S2CID 15142600.
16. Pevsner J, Hsu SC, Scheller RH (February 1994). "n-Sec1: a neural-specific syntaxin-binding protein". Proceedings of the National Academy of Sciences of the United States of America. 91 (4): 1445–1449. Bibcode:1994PNAS...91.1445P. doi:10.1073/pnas.91.4.1445. PMC 43176. PMID 8108429.
17. STXBP1 – this is what you need to know in 2015
18. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, et al. (December 2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell & Melanoma Research. 21 (6): 665–676. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971. S2CID 24698373.
19. Schraw TD, Lemons PP, Dean WL, Whiteheart SW (August 2003). "A role for Sec1/Munc18 proteins in platelet exocytosis". The Biochemical Journal. 374 (Pt 1): 207–217. doi:10.1042/BJ20030610. PMC 1223584. PMID 12773094.
20. Hata Y, Südhof TC (June 1995). "A novel ubiquitous form of Munc-18 interacts with multiple syntaxins. Use of the yeast two-hybrid system to study interactions between proteins involved in membrane traffic". The Journal of Biological Chemistry. 270 (22): 13022–13028. doi:10.1074/jbc.270.22.13022. PMID 7768895.
21. Bhaskar K, Shareef MM, Sharma VM, Shetty AP, Ramamohan Y, Pant HC, et al. (January 2004). "Co-purification and localization of Munc18-1 (p67) and Cdk5 with neuronal cytoskeletal proteins". Neurochemistry International. 44 (1): 35–44. doi:10.1016/S0197-0186(03)00099-8. PMID 12963086. S2CID 23783141.
22. Dulubova I, Sugita S, Hill S, Hosaka M, Fernandez I, Südhof TC, Rizo J (August 1999). "A conformational switch in syntaxin during exocytosis: role of munc18". The EMBO Journal. 18 (16): 4372–4382. doi:10.1093/emboj/18.16.4372. PMC 1171512. PMID 10449403.
23. McMahon HT, Missler M, Li C, Südhof TC (October 1995). "Complexins: cytosolic proteins that regulate SNAP receptor function". Cell. 83 (1): 111–119. doi:10.1016/0092-8674(95)90239-2. PMID 7553862. S2CID 675343.
24. Pérez-Brangulí F, Muhaisen A, Blasi J (June 2002). "Munc 18a binding to syntaxin 1A and 1B isoforms defines its localization at the plasma membrane and blocks SNARE assembly in a three-hybrid system assay". Molecular and Cellular Neurosciences. 20 (2): 169–180. doi:10.1006/mcne.2002.1122. PMID 12093152. S2CID 23927545.

External links

• Overview of all the structural information available in the PDB for UniProt: P61765 (Rat Syntaxin-binding protein 1) at the PDBe-KB.

Further reading

• Barcia G, Barnerias C, Rio M, Siquier-Pernet K, Desguerre I, Colleaux L, et al. (December 2013). "A novel mutation in STXBP1 causing epileptic encephalopathy (late onset infantile spasms) with partial respiratory chain complex IV deficiency". European Journal of Medical Genetics. 56 (12): 683–685. doi:10.1016/j.ejmg.2013.09.013. PMID 24095819.
• Garcia EP, McPherson PS, Chilcote TJ, Takei K, De Camilli P (April 1995). "rbSec1A and B colocalize with syntaxin 1 and SNAP-25 throughout the axon, but are not in a stable complex with syntaxin". The Journal of Cell Biology. 129 (1): 105–120. doi:10.1083/jcb.129.1.105. PMC 2120371. PMID 7698978.
• Pevsner J, Hsu SC, Scheller RH (February 1994). "n-Sec1: a neural-specific syntaxin-binding protein". Proceedings of the National Academy of Sciences of the United States of America. 91 (4): 1445–1449. Bibcode:1994PNAS...91.1445P. doi:10.1073/pnas.91.4.1445. PMC 43176. PMID 8108429.
• Fujita Y, Sasaki T, Fukui K, Kotani H, Kimura T, Hata Y, et al. (March 1996). "Phosphorylation of Munc-18/n-Sec1/rbSec1 by protein kinase C: its implication in regulating the interaction of Munc-18/n-Sec1/rbSec1 with syntaxin". The Journal of Biological Chemistry. 271 (13): 7265–7268. doi:10.1074/jbc.271.13.7265. PMID 8631738.
• Gengyo-Ando K, Kitayama H, Mukaida M, Ikawa Y (November 1996). "A murine neural-specific homolog corrects cholinergic defects in Caenorhabditis elegans unc-18 mutants". The Journal of Neuroscience. 16 (21): 6695–6702. doi:10.1523/jneurosci.16-21-06695.1996. PMC 6579271. PMID 8824310.
• Tellam JT, Macaulay SL, McIntosh S, Hewish DR, Ward CW, James DE (March 1997). "Characterization of Munc-18c and syntaxin-4 in 3T3-L1 adipocytes. Putative role in insulin-dependent movement of GLUT-4". The Journal of Biological Chemistry. 272 (10): 6179–6186. doi:10.1074/jbc.272.10.6179. PMID 9045631.
• Verhage M, de Vries KJ, Røshol H, Burbach JP, Gispen WH, Südhof TC (March 1997). "DOC2 proteins in rat brain: complementary distribution and proposed function as vesicular adapter proteins in early stages of secretion". Neuron. 18 (3): 453–461. doi:10.1016/S0896-6273(00)81245-3. PMID 9115738. S2CID 17948539.
• Okamoto M, Südhof TC (December 1997). "Mints, Munc18-interacting proteins in synaptic vesicle exocytosis". The Journal of Biological Chemistry. 272 (50): 31459–31464. doi:10.1074/jbc.272.50.31459. PMID 9395480.
• Fletcher AI, Shuang R, Giovannucci DR, Zhang L, Bittner MA, Stuenkel EL (February 1999). "Regulation of exocytosis by cyclin-dependent kinase 5 via phosphorylation of Munc18". The Journal of Biological Chemistry. 274 (7): 4027–4035. doi:10.1074/jbc.274.7.4027. PMID 9933594.
• Reed GL, Houng AK, Fitzgerald ML (April 1999). "Human platelets contain SNARE proteins and a Sec1p homologue that interacts with syntaxin 4 and is phosphorylated after thrombin activation: implications for platelet secretion". Blood. 93 (8): 2617–2626. doi:10.1182/blood.V93.8.2617. PMID 10194441.
• Dulubova I, Sugita S, Hill S, Hosaka M, Fernandez I, Südhof TC, Rizo J (August 1999). "A conformational switch in syntaxin during exocytosis: role of munc18". The EMBO Journal. 18 (16): 4372–4382. doi:10.1093/emboj/18.16.4372. PMC 1171512. PMID 10449403.
• Misura KM, Scheller RH, Weis WI (March 2000). "Three-dimensional structure of the neuronal-Sec1-syntaxin 1a complex". Nature. 404 (6776): 355–362. Bibcode:2000Natur.404..355M. doi:10.1038/35006120. PMID 10746715. S2CID 4389052.
• Allan BB, Moyer BD, Balch WE (July 2000). "Rab1 recruitment of p115 into a cis-SNARE complex: programming budding COPII vesicles for fusion". Science. 289 (5478): 444–448. Bibcode:2000Sci...289..444A. doi:10.1126/science.289.5478.444. PMID 10903204.
• Shorter J, Beard MB, Seemann J, Dirac-Svejstrup AB, Warren G (April 2002). "Sequential tethering of Golgins and catalysis of SNAREpin assembly by the vesicle-tethering protein p115". The Journal of Cell Biology. 157 (1): 45–62. doi:10.1083/jcb.200112127. PMC 2173270. PMID 11927603.
• Ho CS, Marinescu V, Steinhilb ML, Gaut JR, Turner RS, Stuenkel EL (July 2002). "Synergistic effects of Munc18a and X11 proteins on amyloid precursor protein metabolism". The Journal of Biological Chemistry. 277 (30): 27021–27028. doi:10.1074/jbc.M201823200. PMID 12016213.
• Pérez-Brangulí F, Muhaisen A, Blasi J (June 2002). "Munc 18a binding to syntaxin 1A and 1B isoforms defines its localization at the plasma membrane and blocks SNARE assembly in a three-hybrid system assay". Molecular and Cellular Neurosciences. 20 (2): 169–180. doi:10.1006/mcne.2002.1122. PMID 12093152. S2CID 23927545.
• Barclay JW, Craig TJ, Fisher RJ, Ciufo LF, Evans GJ, Morgan A, Burgoyne RD (March 2003). "Phosphorylation of Munc18 by protein kinase C regulates the kinetics of exocytosis". The Journal of Biological Chemistry. 278 (12): 10538–10545. doi:10.1074/jbc.M211114200. PMID 12519779.
• Fukuda M (April 2003). "Slp4-a/granuphilin-a inhibits dense-core vesicle exocytosis through interaction with the GDP-bound form of Rab27A in PC12 cells". The Journal of Biological Chemistry. 278 (17): 15390–15396. doi:10.1074/jbc.M213090200. PMID 12590134.
• Craig TJ, Evans GJ, Morgan A (September 2003). "Physiological regulation of Munc18/nSec1 phosphorylation on serine-313". Journal of Neurochemistry. 86 (6): 1450–1457. doi:10.1046/j.1471-4159.2003.01955.x. PMID 12950453. S2CID 27300700.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.