OST Family

Members of the Organic Solute Transporter (OST) family (TC# 2.A.82) (Slc51 genes) have been characterized from a small bottom feeding species of fish called the little skate, Raja erinacea.[1] Members have also been characterized from humans and mice.[2] The OST family is a member of the larger group of secondary carriers, the APC superfamily.

Substrates

Substrates for OST transporters include a variety of organic compounds, most being anionic. Transport of estrone sulfate by the two subunit Ost transporter of Raja erinacea (TC# 2.A.82.1.1) is Na+-independent, ATP-independent, saturable and inhibited by other steroids and anionic drugs. Bile acids such as taurocholate as well as digoxin and prostaglandin E2 are substrates of this system, while estradiol 17β-D-glucuronide and p-aminohippurate are apparently not.[3] Mammalian homologues (e.g., 2.A.82.1.2) similarly exhibit broad substrate specificity, transporting the same compounds, possibly by an anion:anion exchange mechanism.[4][5]

Transport Reaction

The generalized transport reaction catalyzed by OSTα/OSTβ is:[3]

organic anion (out) ⇌ organic anion (in)

Structure

Each transport system consists of two polypeptide chains, designated α and β. For the human protein (TC# 2.A.82.1.2), the α-subunit is of 340 amino acyl residues (aas) with 7 putative transmembrane segments (TMSs) while the β-subunit is of 128 aas with 1 putative TMS near the N-terminus (residues 40-56). Neither OSTα nor OSTβ alone has activity, both serving not only for heterodimerization and trafficking but also for function.[6] The two proteins are highly expressed in many human tissues. The β-subunit is not required to target the α-subunit to the plasma membrane, but coexpression of both genes is required to convert OSTα to the mature glycosylated protein in enterocyte basolateral membranes and possibly for trafficking through the golgi apparatus.[7] OSTαβ proteins are made in a variety of tissues including the small intestine, colon, liver, biliary tract, kidney, and adrenal gland. In polarized epithelial cells, they are localized to the basolateral membrane and function in the export or uptake of bile acids and steroids.[8] Homologues of OSTα are found in many eukaryotes including animals (both vertebrates and invertebrates), plants, fungi and slime molds. Homologues of OSTβ are found only in vertebrate animals.[3]

Crystal Structures

As of early 2016, no crystal structures had been determined. However, bioinformatics utilizing combinations of homology modelling and mutation experiments have been used to explore the heterdimer nature of the system as well as the mechanisms of substrate recognition and transport.[9]

See also

References

  1. ↑ Wang, W; Seward, DJ; Li, L; Boyer, JL; Ballatori, N (July 31, 2001). "Expression cloning of two genes that together mediate organic solute and steroid transport in the liver of a marine vertebrate.". Proceedings of the National Academy of Sciences USA 98 (16): 9431–6. PMID 11470901.
  2. ↑ Seward, DJ; Koh, AS; Boyer, JL; Ballatori, N (July 25, 2003). "Functional complementation between a novel mammalian polygenic transport complex and an evolutionarily ancient organic solute transporter, OSTalpha-OSTbeta.". Journal of Biological Chemistry 278 (30): 27473–82. PMID 12719432.
  3. 1 2 3 Saier, Milton. "Transporter Classification Database: 2.A.82 The Organic Solute Transporter (OST) Family". tcdb.org.
  4. ↑ Ballatori, Nazzareno; Christian, Whitney V.; Wheeler, Sadie G.; Hammond, Christine L. (2013-04-01). "The heteromeric organic solute transporter, OSTα–OSTβ/SLC51: A transporter for steroid-derived molecules". Molecular Aspects of Medicine. The ABCs of membrane transporters in health and disease (SLC series) 34 (2–3): 683–692. doi:10.1016/j.mam.2012.11.005. PMC 3827772. PMID 23506901.
  5. ↑ Dawson, Paul A.; Hubbert, Melissa; Haywood, Jamie; Craddock, Ann L.; Zerangue, Noa; Christian, Whitney V.; Ballatori, Nazzareno (2005-02-25). "The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter". The Journal of Biological Chemistry 280 (8): 6960–6968. doi:10.1074/jbc.M412752200. ISSN 0021-9258. PMC 1224727. PMID 15563450.
  6. ↑ Christian, WV; Li, N; Hinkle, PM; Ballatori, N (June 15, 2012). "β-Subunit of the Ostα-Ostβ organic solute transporter is required not only for heterodimerization and trafficking but also for function.". Journal of Biological Chemistry 287 (25): 21233–43. doi:10.1074/jbc.M112.352245. PMID 22535958.
  7. ↑ Dawson, PA; Hubbert, M; Haywood, J; Craddock, AL; Zerangue, N; Christian, WV; Ballatori, N (Feb 25, 2005). "The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter.". J Biol Chem. 280 (8): 6960–8. PMID 15563450.
  8. ↑ Dawson, PA; Hubbert, ML; Rao, A (September 2010). "Getting the mOST from OST: Role of organic solute transporter, OSTalpha-OSTbeta, in bile acid and steroid metabolism.". Biochim Biophys Acta 1801 (9): 994–1004. doi:10.1016/j.bbalip.2010.06.002. PMID 20538072.
  9. ↑ Roth B., M; Obaidat, A; Hagenbuch, B (March 2012). "OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies". British Journal of Pharmacology 165 (5): 1260–87. doi:10.1111/j.1476-5381.2011.01724.x. PMID 22013971.

Further reading

  • Ballatori, N; Christian, WV; Wheeler, SG; Hammond, CL (2013). "The heteromeric organic solute transporter, OSTα-OSTβ/SLC51: a transporter for steroid-derived molecules.". Mol Aspects Med. 34 (2-3): 23506901. doi:10.1016/j.mam.2012.11.005. 
  • Lan, T; Haywood, J; Rao, A; Dawson, P (2011). "Molecular Mechanisms of Altered Bile Acid Homeostasis in Organic Solute Transporter-Alpha Knockout Mice". Digestive Diseases 29 (1). doi:10.1159/000324124. 
  • Rao, A; Haywood, J; Craddock, A; Belinsky, M; Kruh, G; Dawson, P (December 28, 2007). "The organic solute transporter α-β, Ostα-Ostβ, is essential for intestinal bile acid transport and homeostasis". Proceedings of the National Academy of Sciences USA 105 (10): 3891–3896. doi:10.1073/pnas.0712328105. 


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