STXBP1 explained

Syntaxin-binding protein 1 (also known as Munc18-1) is a protein that in humans is encoded by the STXBP1 gene.[1] 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.[2] [3] [4] [5]

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.[2] The encoded protein is a peripheral membrane protein located in the cytosol.[6] [7] In the retina and cerebellum, an alternatively spliced transcript variant is expressed, containing an additional exon and totaling 603 amino acids.[1] Alternative splicing can produce an isoform with exon 19 and an isoform without.[8] [9]

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. 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.[10] This protein is essential for presynpatic vesicle release and is rapidly phosphorylated by protein kinase C upon neuronal depolarization.[11] The protein participates in the secretory pathway between the Golgi apparatus and cell membrane.[12]

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. Inheritance of EIEE4 is autosomal dominant, but due to the severity of the condition most cases are de novo.

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.[13]

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.

Expression

In melanocytic cells STXBP1 gene expression may be regulated by MITF.[14]

The STXBP1 gene is expressed in the brain and spinal cord and highly enriched in axons. Expression of this protein is highest in the retina and cerebellum.[1]

Interactions

The encoded protein binds SYTL4. STXBP1 has been shown to interact with STX2,[15] [16] STX4 and STX1A.[16] [17] [18] [19] [20]

External links

Further reading

Notes and References

  1. Swanson DA, Steel JM, Valle D . Identification and characterization of the human ortholog of rat STXBP1, a protein implicated in vesicle trafficking and neurotransmitter release . Genomics . 48 . 3 . 373–376 . March 1998 . 9545644 . 10.1006/geno.1997.5202 . free .
  2. Web site: Entrez Gene: STXBP1 syntaxin binding protein 1. 2018-08-29.
  3. Stamberger H, Nikanorova M, Willemsen MH, Accorsi P, Angriman M, Baier H, Benkel-Herrenbrueck I, Benoit V, Budetta M, Caliebe A, Cantalupo G, Capovilla G, Casara G, Courage C, Deprez M, Destrée A, Dilena R, Erasmus CE, Fannemel M, Fjær R, Giordano L, Helbig KL, Heyne HO, Klepper J, Kluger GJ, Lederer D, Lodi M, Maier O, Merkenschlager A, Michelberger N, Minetti C, Muhle H, Phalin J, Ramsey K, Romeo A, Schallner J, Schanze I, Shinawi M, Sleegers K, Sterbova K, Syrbe S, Traverso M, Tzschach A, Uldall P, Van Coster R, Verhelst H, Viri M, Winter S, Wolff M, Zenker M, Zoccante L, De Jonghe P, Helbig I, Striano P, Lemke JR, Møller RS, Weckhuysen S . 6 . STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy . Neurology . 86 . 10 . 954–962 . March 2016 . 26865513 . 10.1212/WNL.0000000000002457 . 26206858 . 10067/1331590151162165141 . free .
  4. Stamberger H, Crosiers D, Balagura G, Bonardi CM, Basu A, Cantalupo G, Chiesa V, Christensen J, Dalla Bernardina B, Ellis CA, Furia F, Gardiner F, Giron C, Guerrini R, Klein KM, Korff C, Krijtova H, Leffner M, Lerche H, Lesca G, Lewis-Smith D, Marini C, Marjanovic D, Mazzola L, McKeown Ruggiero S, Mochel F, Ramond F, Reif PS, Richard-Mornas A, Rosenow F, Schropp C, Thomas RH, Vignoli A, Weber Y, Palmer E, Helbig I, Scheffer IE, Striano P, Møller RS, Gardella E, Weckhuysen S . 6 . Natural History Study of STXBP1-Developmental and Epileptic Encephalopathy Into Adulthood . Neurology . 99 . 3 . e221–e233 . July 2022 . 35851549 . 9302932 . 10.1212/WNL.0000000000200715 .
  5. 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 . en . 837–840 . 10.1002/mdc3.13509 . 35937496 . 9346254 . 1983/6fcc0c91-524a-4455-8291-61c09eea4332 . 2330-1619.
  6. Web site: STXBP1 -Syntaxin-binding protein 1 - Homo sapiens (Human) - STXBP1 gene & protein. www.uniprot.org. en. 2018-08-29.
  7. UniProt: the universal protein knowledgebase . Nucleic Acids Research . 45 . D1 . D158–D169 . January 2017 . 27899622 . 5210571 . 10.1093/nar/gkw1099 .
  8. Hamdan FF, Piton A, Gauthier J, Lortie A, Dubeau F, Dobrzeniecka S, Spiegelman D, Noreau A, Pellerin S, Côté M, Henrion E, Fombonne E, Mottron L, Marineau C, Drapeau P, Lafrenière RG, Lacaille JC, Rouleau GA, Michaud JL . 6 . De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy . Annals of Neurology . 65 . 6 . 748–753 . June 2009 . 19557857 . 10.1002/ana.21625 . 23892974 .
  9. Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: : : . World Wide Web URL: https://omim.org/
  10. Fisher RJ, Pevsner J, Burgoyne RD . Control of fusion pore dynamics during exocytosis by Munc18 . Science . 291 . 5505 . 875–878 . February 2001 . 11157167 . 10.1126/science.291.5505.875 . 2001Sci...291..875F . 27780447 .
  11. Wierda KD, Toonen RF, de Wit H, Brussaard AB, Verhage M . Interdependence of PKC-dependent and PKC-independent pathways for presynaptic plasticity . Neuron . 54 . 2 . 275–290 . April 2007 . 17442248 . 10.1016/j.neuron.2007.04.001 . 15142600 . free .
  12. Pevsner J, Hsu SC, Scheller RH . 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 . February 1994 . 8108429 . 43176 . 10.1073/pnas.91.4.1445 . 1994PNAS...91.1445P . free .
  13. http://epilepsygenetics.net/2015/08/04/stxbp1-this-is-what-you-need-to-know-in-2015/ STXBP1 – this is what you need to know in 2015
  14. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E . 6 . Novel MITF targets identified using a two-step DNA microarray strategy . Pigment Cell & Melanoma Research . 21 . 6 . 665–676 . December 2008 . 19067971 . 10.1111/j.1755-148X.2008.00505.x . 24698373 . free .
  15. Schraw TD, Lemons PP, Dean WL, Whiteheart SW . A role for Sec1/Munc18 proteins in platelet exocytosis . The Biochemical Journal . 374 . Pt 1 . 207–217 . August 2003 . 12773094 . 1223584 . 10.1042/BJ20030610 .
  16. Hata Y, Südhof TC . 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 . June 1995 . 7768895 . 10.1074/jbc.270.22.13022 . free .
  17. Bhaskar K, Shareef MM, Sharma VM, Shetty AP, Ramamohan Y, Pant HC, Raju TR, Shetty KT . 6 . Co-purification and localization of Munc18-1 (p67) and Cdk5 with neuronal cytoskeletal proteins . Neurochemistry International . 44 . 1 . 35–44 . January 2004 . 12963086 . 10.1016/S0197-0186(03)00099-8 . 23783141 .
  18. Dulubova I, Sugita S, Hill S, Hosaka M, Fernandez I, Südhof TC, Rizo J . A conformational switch in syntaxin during exocytosis: role of munc18 . The EMBO Journal . 18 . 16 . 4372–4382 . August 1999 . 10449403 . 1171512 . 10.1093/emboj/18.16.4372 .
  19. McMahon HT, Missler M, Li C, Südhof TC . Complexins: cytosolic proteins that regulate SNAP receptor function . Cell . 83 . 1 . 111–119 . October 1995 . 7553862 . 10.1016/0092-8674(95)90239-2 . 675343 . free .
  20. Pérez-Brangulí F, Muhaisen A, Blasi J . 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 . June 2002 . 12093152 . 10.1006/mcne.2002.1122 . 23927545 .

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