Wikipedia

STXBP1

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]

STXBP1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesSTXBP1, MUNC18-1, NSEC1, P67, RBSEC1, UNC18, syntaxin binding protein 1
External IDsOMIM: 602926; MGI: 107363; HomoloGene: 2382; GeneCards: STXBP1; OMA:STXBP1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

6812

20910

Ensembl

ENSG00000136854

ENSMUSG00000026797

UniProt

P61764

O08599

RefSeq (mRNA)

NM_003165
NM_001032221

NM_001113569
NM_009295

RefSeq (protein)

NP_001107041
NP_033321

Location (UCSC)Chr 9: 127.58 – 127.7 MbChr 2: 32.68 – 32.74 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure

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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

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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

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Epilepsy

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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

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

Expression

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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

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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

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000136854 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b c 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. ^ a b c "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. ^ a b 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. ^ a b c 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. ^ a b 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. ^ a b c d e "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. ^ a b c d e "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. ^ a b c 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. ^ a b 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. ^ a b c 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.
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  • Overview of all the structural information available in the PDB for UniProt: P61765 (Rat Syntaxin-binding protein 1) at the PDBe-KB.

Further reading

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

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