STX1A explained

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

Function

Synaptic vesicles store neurotransmitters that are released during calcium-regulated exocytosis. The specificity of neurotransmitter release requires the localization of both synaptic vesicles and calcium channels to the presynaptic active zone. Syntaxins function in this vesicle fusion process.

Syntaxin-1A is a member of the syntaxin superfamily. Syntaxins are nervous system-specific proteins implicated in the docking of synaptic vesicles with the presynaptic plasma membrane. Syntaxins possess a single C-terminal transmembrane domain, a SNARE [Soluble NSF (N-ethylmaleimide-sensitive fusion protein)-Attachment protein REceptor] domain (known as H3), and an N-terminal regulatory domain (Habc). Syntaxins bind synaptotagmin in a calcium-dependent fashion and interact with voltage dependent calcium and potassium channels via the C-terminal H3 domain. Syntaxin-1A is a key protein in ion channel regulation and synaptic exocytosis.^[2]

Clinical significance

Syntaxins serve as a substrate for botulinum neurotoxin type C, a metalloprotease that blocks exocytosis and has high affinity for a molecular complex that includes the alpha-latrotoxin receptor which produces explosive exocytosis.^[3]

The expression level of STX1A is directly correlated with intelligence in Williams syndrome.^[4]

Interactions

STX1A has been shown to interact with:

• CPLX1,^[5]
• CFTR,^{[6] [7]}
• NAPA,^[8]
• RNF40,^[9]
• SCNN1G,^[10]
• SLC6A1,^{[11] [12] [13]}
• SNAP-25,^{[14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24]}
• SNAP23,^{[22] [24] [25] [26] [27]}
• STXBP1,^{[14] [16] [18] [28]}
• STXBP5,^{[29] [30]}
• SYT1^{[31] [32]}
• UNC13B,^[33]
• VAMP2,^{[14] [15] [16] [34] [35] [36]} and
• VAMP8.^[37]

See also

• Syntaxin

Further reading

• Peters KW, Qi J, Johnson JP, Watkins SC, Frizzell RA . Role of snare proteins in CFTR and ENaC trafficking . Pflügers Archiv . 443 . S65–9 . 2002 . Suppl 1 . 11845306 . 10.1007/s004240100647 . 21790638 .
• Wilson DW, Whiteheart SW, Wiedmann M, Brunner M, Rothman JE . A multisubunit particle implicated in membrane fusion . The Journal of Cell Biology . 117 . 3 . 531–8 . May 1992 . 1315316 . 2289450 . 10.1083/jcb.117.3.531 .
• McMahon HT, Missler M, Li C, Südhof TC . Complexins: cytosolic proteins that regulate SNAP receptor function . Cell . 83 . 1 . 111–9 . October 1995 . 7553862 . 10.1016/0092-8674(95)90239-2 . 675343 . free .
• Zhang R, Maksymowych AB, Simpson LL . Cloning and sequence analysis of a cDNA encoding human syntaxin 1A, a polypeptide essential for exocytosis . Gene . 159 . 2 . 293–4 . July 1995 . 7622072 . 10.1016/0378-1119(95)00152-V .
• Hanson PI, Otto H, Barton N, Jahn R . The N-ethylmaleimide-sensitive fusion protein and alpha-SNAP induce a conformational change in syntaxin . The Journal of Biological Chemistry . 270 . 28 . 16955–61 . July 1995 . 7622514 . 10.1074/jbc.270.28.16955 . free .
• 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 . 13022–8 . June 1995 . 7768895 . 10.1074/jbc.270.22.13022 . free .
• Li C, Ullrich B, Zhang JZ, Anderson RG, Brose N, Südhof TC . Ca(2+)-dependent and -independent activities of neural and non-neural synaptotagmins . Nature . 375 . 6532 . 594–9 . June 1995 . 7791877 . 10.1038/375594a0 . 1995Natur.375..594L . 4265549 .
• 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 . 1445–9 . February 1994 . 8108429 . 43176 . 10.1073/pnas.91.4.1445 . 1994PNAS...91.1445P . free .
• Betz A, Okamoto M, Benseler F, Brose N . Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin . The Journal of Biological Chemistry . 272 . 4 . 2520–6 . January 1997 . 8999968 . 10.1074/jbc.272.4.2520 . free .
• Jagadish MN, Tellam JT, Macaulay SL, Gough KH, James DE, Ward CW . Novel isoform of syntaxin 1 is expressed in mammalian cells . The Biochemical Journal . 321 (Pt 1) . Pt 1 . 151–6 . January 1997 . 9003414 . 1218049 . 10.1042/bj3210151.
• Shao X, Li C, Fernandez I, Zhang X, Südhof TC, Rizo J . Synaptotagmin-syntaxin interaction: the C2 domain as a Ca2+-dependent electrostatic switch . Neuron . 18 . 1 . 133–42 . January 1997 . 9010211 . 10.1016/S0896-6273(01)80052-0 . 17947552 . free .
• Hao JC, Salem N, Peng XR, Kelly RB, Bennett MK . Effect of mutations in vesicle-associated membrane protein (VAMP) on the assembly of multimeric protein complexes . The Journal of Neuroscience . 17 . 5 . 1596–603 . March 1997 . 9030619 . 6573372 . 10.1523/JNEUROSCI.17-05-01596.1997.
• Tellam JT, Macaulay SL, McIntosh S, Hewish DR, Ward CW, James DE . 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 . 6179–86 . March 1997 . 9045631 . 10.1074/jbc.272.10.6179 . free .
• Coffield JA, Bakry N, Zhang RD, Carlson J, Gomella LG, Simpson LL . In vitro characterization of botulinum toxin types A, C and D action on human tissues: combined electrophysiologic, pharmacologic and molecular biologic approaches . The Journal of Pharmacology and Experimental Therapeutics . 280 . 3 . 1489–98 . March 1997 . 9067339 .
• Nakayama T, Fujiwara T, Miyazawa A, Asakawa S, Shimizu N, Shimizu Y, Mikoshiba K, Akagawa K . Mapping of the human HPC-1/syntaxin 1A gene (STX1A) to chromosome 7 band q11.2 . Genomics . 42 . 1 . 173–6 . May 1997 . 9177791 . 10.1006/geno.1997.4650 .
• Osborne LR, Soder S, Shi XM, Pober B, Costa T, Scherer SW, Tsui LC . Hemizygous deletion of the syntaxin 1A gene in individuals with Williams syndrome . American Journal of Human Genetics . 61 . 2 . 449–52 . August 1997 . 9311751 . 1715888 . 10.1086/514850 .
• Naren AP, Nelson DJ, Xie W, Jovov B, Pevsner J, Bennett MK, Benos DJ, Quick MW, Kirk KL . Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms . Nature . 390 . 6657 . 302–5 . November 1997 . 9384384 . 10.1038/36882 . 1997Natur.390..302N . 4395005 .
• Okamoto M, Südhof TC . Mints, Munc18-interacting proteins in synaptic vesicle exocytosis . The Journal of Biological Chemistry . 272 . 50 . 31459–64 . December 1997 . 9395480 . 10.1074/jbc.272.50.31459 . free .
• Shuang R, Zhang L, Fletcher A, Groblewski GE, Pevsner J, Stuenkel EL . Regulation of Munc-18/syntaxin 1A interaction by cyclin-dependent kinase 5 in nerve endings . The Journal of Biological Chemistry . 273 . 9 . 4957–66 . February 1998 . 9478941 . 10.1074/jbc.273.9.4957 . free .
• Vinogradova TI . [Destructive tuberculosis of the lung in adolescents] . ru . Problemy Tuberkuleza . 1 . 19–22 . January 1977 . 834751 .
• Burgess RW, Deitcher DL, Schwarz TL . The synaptic protein syntaxin1 is required for cellularization of Drosophila embryos . The Journal of Cell Biology . 138 . 4 . 861–75 . August 1997 . 9265652 . 2138053 . 10.1083/jcb.138.4.861 .
• Littleton JT, Chapman ER, Kreber R, Garment MB, Carlson SD, Ganetzky B . Temperature-sensitive paralytic mutations demonstrate that synaptic exocytosis requires SNARE complex assembly and disassembly . Neuron . 21 . 2 . 401–13 . August 1998 . 9728921 . 10.1016/S0896-6273(00)80549-8 . 15119362 . free .
• Lagow RD, Bao H, Cohen EN, Daniels RW, Zuzek A, Williams WH, Macleod GT, Sutton RB, Zhang B . Modification of a hydrophobic layer by a point mutation in syntaxin 1A regulates the rate of synaptic vesicle fusion . PLOS Biology . 5 . 4 . e72 . April 2007 . 17341138 . 1808484 . 10.1371/journal.pbio.0050072 . free .

Notes and References

1. Bennett MK, Calakos N, Scheller RH . Syntaxin: a synaptic protein implicated in docking of synaptic vesicles at presynaptic active zones . Science . 257 . 5067 . 255–9 . July 1992 . 1321498 . 10.1126/science.1321498 . 1992Sci...257..255B .
2. Web site: Entrez Gene: STX1A syntaxin 1A (brain).
3. Zhang R, Maksymowych AB, Simpson LL . Cloning and sequence analysis of a cDNA encoding human syntaxin 1A, a polypeptide essential for exocytosis . Gene . 159 . 2 . 293–4 . July 1995 . 7622072 . 10.1016/0378-1119(95)00152-V .
4. Gao MC, Bellugi U, Dai L, Mills DL, Sobel EM, Lange K, Korenberg JR . Intelligence in Williams Syndrome is related to STX1A, which encodes a component of the presynaptic SNARE complex . PLOS ONE . 5 . 4 . e10292 . 2010 . 20422020 . 2858212 . 10.1371/journal.pone.0010292 . 2010PLoSO...510292G . Toland . Amanda Ewart . free .
   • News: Brian Maffly . 2010-04-22 . U. scientist links one gene to intelligence . The Salt Lake Tribune . https://web.archive.org/web/20100425054909/http://www.sltrib.com/news/ci_14932330 . 2010-04-25.
5. Hu K, Carroll J, Rickman C, Davletov B . Action of complexin on SNARE complex . The Journal of Biological Chemistry . 277 . 44 . 41652–6 . November 2002 . 12200427 . 10.1074/jbc.M205044200 . free .
6. Naren AP, Nelson DJ, Xie W, Jovov B, Pevsner J, Bennett MK, Benos DJ, Quick MW, Kirk KL . Regulation of CFTR chloride channels by syntaxin and Munc18 isoforms . Nature . 390 . 6657 . 302–5 . November 1997 . 9384384 . 10.1038/36882 . 1997Natur.390..302N . 4395005 .
7. Cormet-Boyaka E, Di A, Chang SY, Naren AP, Tousson A, Nelson DJ, Kirk KL . CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex . Proceedings of the National Academy of Sciences of the United States of America . 99 . 19 . 12477–82 . September 2002 . 12209004 . 129470 . 10.1073/pnas.192203899 . 2002PNAS...9912477C . free .
8. Hanson PI, Otto H, Barton N, Jahn R . The N-ethylmaleimide-sensitive fusion protein and alpha-SNAP induce a conformational change in syntaxin . The Journal of Biological Chemistry . 270 . 28 . 16955–61 . July 1995 . 7622514 . 10.1074/jbc.270.28.16955 . free .
9. Chin LS, Vavalle JP, Li L . Staring, a novel E3 ubiquitin-protein ligase that targets syntaxin 1 for degradation . The Journal of Biological Chemistry . 277 . 38 . 35071–9 . September 2002 . 12121982 . 10.1074/jbc.M203300200 . free .
10. Berdiev BK, Jovov B, Tucker WC, Naren AP, Fuller CM, Chapman ER, Benos DJ . ENaC subunit-subunit interactions and inhibition by syntaxin 1A . American Journal of Physiology. Renal Physiology . 286 . 6 . F1100–6 . June 2004 . 14996668 . 10.1152/ajprenal.00344.2003 . 18384316 .
11. Beckman ML, Bernstein EM, Quick MW . Protein kinase C regulates the interaction between a GABA transporter and syntaxin 1A . The Journal of Neuroscience . 18 . 16 . 6103–12 . August 1998 . 9698305 . 6793212 . 10.1523/JNEUROSCI.18-16-06103.1998.
12. Quick MW . Substrates regulate gamma-aminobutyric acid transporters in a syntaxin 1A-dependent manner . Proceedings of the National Academy of Sciences of the United States of America . 99 . 8 . 5686–91 . April 2002 . 11960023 . 122832 . 10.1073/pnas.082712899 . 2002PNAS...99.5686Q . free .
13. Deken SL, Beckman ML, Boos L, Quick MW . Transport rates of GABA transporters: regulation by the N-terminal domain and syntaxin 1A . Nature Neuroscience . 3 . 10 . 998–1003 . October 2000 . 11017172 . 10.1038/79939 . 11312913 .
14. 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 . 4372–82 . August 1999 . 10449403 . 1171512 . 10.1093/emboj/18.16.4372 .
15. Chen X, Tomchick DR, Kovrigin E, Araç D, Machius M, Südhof TC, Rizo J . Three-dimensional structure of the complexin/SNARE complex . Neuron . 33 . 3 . 397–409 . January 2002 . 11832227 . 10.1016/S0896-6273(02)00583-4 . 17878965 . free .
16. McMahon HT, Missler M, Li C, Südhof TC . Complexins: cytosolic proteins that regulate SNAP receptor function . Cell . 83 . 1 . 111–9 . October 1995 . 7553862 . 10.1016/0092-8674(95)90239-2 . 675343 . free .
17. Stelzl U, Worm U, Lalowski M, Haenig C, Brembeck FH, Goehler H, Stroedicke M, Zenkner M, Schoenherr A, Koeppen S, Timm J, Mintzlaff S, Abraham C, Bock N, Kietzmann S, Goedde A, Toksöz E, Droege A, Krobitsch S, Korn B, Birchmeier W, Lehrach H, Wanker EE . A human protein-protein interaction network: a resource for annotating the proteome . Cell . 122 . 6 . 957–68 . September 2005 . 16169070 . 10.1016/j.cell.2005.08.029 . 11858/00-001M-0000-0010-8592-0 . 8235923 . free .
18. 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 . 13022–8 . June 1995 . 7768895 . 10.1074/jbc.270.22.13022 . free .
19. Gonelle-Gispert C, Molinete M, Halban PA, Sadoul K . Membrane localization and biological activity of SNAP-25 cysteine mutants in insulin-secreting cells . Journal of Cell Science . 113 (Pt 18) . 18 . 3197–205 . September 2000 . 10.1242/jcs.113.18.3197 . 10954418 .
20. Ilardi JM, Mochida S, Sheng ZH . Snapin: a SNARE-associated protein implicated in synaptic transmission . Nature Neuroscience . 2 . 2 . 119–24 . February 1999 . 10195194 . 10.1038/5673 . 25524692 .
21. Li Y, Chin LS, Weigel C, Li L . Spring, a novel RING finger protein that regulates synaptic vesicle exocytosis . The Journal of Biological Chemistry . 276 . 44 . 40824–33 . November 2001 . 11524423 . 10.1074/jbc.M106141200 . free .
22. Ravichandran V, Chawla A, Roche PA . Identification of a novel syntaxin- and synaptobrevin/VAMP-binding protein, SNAP-23, expressed in non-neuronal tissues . The Journal of Biological Chemistry . 271 . 23 . 13300–3 . June 1996 . 8663154 . 10.1074/jbc.271.23.13300 . free .
23. Chapman ER, An S, Barton N, Jahn R . SNAP-25, a t-SNARE which binds to both syntaxin and synaptobrevin via domains that may form coiled coils . The Journal of Biological Chemistry . 269 . 44 . 27427–32 . November 1994 . 10.1016/S0021-9258(18)47003-2 . 7961655 . free .
24. Steegmaier M, Yang B, Yoo JS, Huang B, Shen M, Yu S, Luo Y, Scheller RH . Three novel proteins of the syntaxin/SNAP-25 family . The Journal of Biological Chemistry . 273 . 51 . 34171–9 . December 1998 . 9852078 . 10.1074/jbc.273.51.34171 . free .
25. Imai A, Nashida T, Yoshie S, Shimomura H . Intracellular localisation of SNARE proteins in rat parotid acinar cells: SNARE complexes on the apical plasma membrane . Archives of Oral Biology . 48 . 8 . 597–604 . August 2003 . 12828989 . 10.1016/S0003-9969(03)00116-X .
26. Li G, Alexander EA, Schwartz JH . Syntaxin isoform specificity in the regulation of renal H+-ATPase exocytosis . The Journal of Biological Chemistry . 278 . 22 . 19791–7 . May 2003 . 12651853 . 10.1074/jbc.M212250200 . free .
27. Araki S, Tamori Y, Kawanishi M, Shinoda H, Masugi J, Mori H, Niki T, Okazawa H, Kubota T, Kasuga M . Inhibition of the binding of SNAP-23 to syntaxin 4 by Munc18c . Biochemical and Biophysical Research Communications . 234 . 1 . 257–62 . May 1997 . 9168999 . 10.1006/bbrc.1997.6560 . 20.500.14094/D2002245 . free .
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29. Widberg CH, Bryant NJ, Girotti M, Rea S, James DE . Tomosyn interacts with the t-SNAREs syntaxin4 and SNAP23 and plays a role in insulin-stimulated GLUT4 translocation . The Journal of Biological Chemistry . 278 . 37 . 35093–101 . September 2003 . 12832401 . 10.1074/jbc.M304261200 . free .
30. Fujita Y, Shirataki H, Sakisaka T, Asakura T, Ohya T, Kotani H, Yokoyama S, Nishioka H, Matsuura Y, Mizoguchi A, Scheller RH, Takai Y . Tomosyn: a syntaxin-1-binding protein that forms a novel complex in the neurotransmitter release process . Neuron . 20 . 5 . 905–15 . May 1998 . 9620695 . 10.1016/S0896-6273(00)80472-9 . 12597505 . free .
31. Shao X, Li C, Fernandez I, Zhang X, Südhof TC, Rizo J . Synaptotagmin-syntaxin interaction: the C2 domain as a Ca2+-dependent electrostatic switch . Neuron . 18 . 1 . 133–42 . January 1997 . 9010211 . 10.1016/S0896-6273(01)80052-0 . 17947552 . free .
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33. Betz A, Okamoto M, Benseler F, Brose N . Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin . The Journal of Biological Chemistry . 272 . 4 . 2520–6 . January 1997 . 8999968 . 10.1074/jbc.272.4.2520 . free .
34. 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 . 169–80 . June 2002 . 12093152 . 10.1006/mcne.2002.1122 . 23927545 .
35. Margittai M, Otto H, Jahn R . A stable interaction between syntaxin 1a and synaptobrevin 2 mediated by their transmembrane domains . FEBS Letters . 446 . 1 . 40–4 . March 1999 . 10100611 . 10.1016/S0014-5793(99)00028-9 . 9115709 . free .
36. Hao JC, Salem N, Peng XR, Kelly RB, Bennett MK . Effect of mutations in vesicle-associated membrane protein (VAMP) on the assembly of multimeric protein complexes . The Journal of Neuroscience . 17 . 5 . 1596–603 . March 1997 . 9030619 . 6573372 . 10.1523/JNEUROSCI.17-05-01596.1997.
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