2.A.82 The Organic Solute Transporter (OST) Family

Members of the OST (Slc51(A)) family have been characterized from the little skate, Raja erinacea (Wang et al., 2001), humans and mice (Seward et al., 2003). Each system consists of two polypeptide chains, α and β. For the human, the α-subunit is of 340 aas with 7 putative TMSs while the β-subunit is of 128 aas with 1 putative TMS near the N-terminus (residues 40-56). The beta subunit is required not only for heterodimerization and trafficking but also for function (Christian et al., 2012).  The functions of the extracellular, transmembrane and cytoplasmic domains have been reported where only the transmembrane domain plus 15 associated amino acyl residues are essential for activity (Christian and Hinkle 2017). Members of this family have been proposed to have the SLC51 fold (Ferrada and Superti-Furga 2022).

Neither OSTα (OSTa) nor OSTβ (OSTb) alone has activity, but the two together transport a variety of organic compounds, mostly anions. Transport of estrone-3-sulfate is Na+-independent, ATP-independent, saturable and inhibited by other steroids and anionic drugs. Bile acids, taurocholate, digoxin and prostaglandin E1 are substrates, but estradiol 17β-D-glucuronide and p-aminohippurate are not. 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 (Dawson et al., 2005). 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 on the basolateral membrane and function in the export or uptake of bile acids and steroids (Dawson et al., 2010). 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.

TC Blast reveals that the human OSTα protein shows limited sequence similarity with the YhhT protein of E. coli (P37622) (30% identity in 100 residues with 4 gaps). YhhT is in the AI2E family (TC # 2.A.86). PerM homologues, members of the AI2E family, are found in bacteria and archaea but not eukaryotes. They also have 7 putative TMSs.

The transport reaction catalyzed by OSTα/OSTβ is:

organic anion (out) ⇌ organic anion (in)


This family belongs to the Transporter-Opsin-G protein-coupled receptor (TOG) Superfamily.
 

References:

Ballatori, N., W.V. Christian, S.G. Wheeler, and C.L. Hammond. (2013). The heteromeric organic solute transporter, OSTα-OSTβ/SLC51: A transporter for steroid-derived molecules. Mol Aspects Med 34: 683-692.
Best, D. and I.R. Adams. (2009). Sdmg1 is a component of secretory granules in mouse secretory exocrine tissues. Dev Dyn 238: 223-231.
Best, D., D.A. Sahlender, N. Walther, A.A. Peden, and I.R. Adams. (2008). Sdmg1 is a conserved transmembrane protein associated with germ cell sex determination and germline-soma interactions in mice. Development 135: 1415-1425.
Christian WV., Li N., Hinkle PM. and Ballatori N. (2012). beta-Subunit of the Ostalpha-Ostbeta organic solute transporter is required not only for heterodimerization and trafficking but also for function. J Biol Chem. 287(25):21233-43.
Christian, W.V. and P.M. Hinkle. (2017). Global functions of extracellular, transmembrane and cytoplasmic domains of organic solute transporter β subunit. Biochem. J. [Epub: Ahead of Print]
Dawson, P.A., M. Hubbert, J. Haywood, A.L. Craddock, N. Zerangue, W.V. Christian, and N. Ballatori. (2005). The heteromeric organic solute transporter α-β, Ostα-Ostβ, is an ileal basolateral bile acid transporter. J. Biol. Chem. 280: 6960-6968.
Dawson, P.A., M.L. Hubbert, and A. Rao. (2010). Getting the mOST from OST: Role of organic solute transporter, OSTα-OSTbeta, in bile acid and steroid metabolism. Biochim. Biophys. Acta. 1801: 994-1004.
Farwell, S.L., D. Kanyi, M. Hamel, J.B. Slee, E.A. Miller, M.D. Cipolle, and L.J. Lowe-Krentz. (2016). Heparin Decreases in Tumor Necrosis Factor α (TNFα)-induced Endothelial Stress Responses Require Transmembrane Protein 184A and Induction of Dual Specificity Phosphatase 1. J. Biol. Chem. 291: 5342-5354.
Ferrada, E. and G. Superti-Furga. (2022). A structure and evolutionary-based classification of solute carriers. iScience 25: 105096.
Liu, B., H. Yu, Q. Yang, L. Ding, F. Sun, J. Qu, W. Feng, Q. Yang, W. Li, and F. Fu. (2022). Zinc Transporter ZmLAZ1-4 Modulates Zinc Homeostasis on Plasma and Vacuolar Membrane in Maize. Front Plant Sci 13: 881055.
Murphy, W.A., J.J. Beaudoin, T. Laitinen, N. Sjöstedt, M.M. Malinen, H. Ho, P.W. Swaan, P. Honkakoski, and K.L. Brouwer. (2021). Identification of Key Amino Acids that Impact Organic Solute Transporter Alpha/Beta (OSTα/β). Mol Pharmacol. [Epub: Ahead of Print]
Rasmussen, R.N., K.V. Christensen, R. Holm, and C.U. Nielsen. (2019). Nfat5 is involved in the hyperosmotic regulation of Tmem184b: a putative modulator of ibuprofen transport in renal MDCK I cells. FEBS Open Bio 9: 1071-1081.
Seward, D.J., A.S. Koh, J.L. Boyer, and N. Ballatori. (2003). Functional complementation between a novel mammalian polygenic transport complex and an evolutionarily ancient organic solute transporter, OSTα-OSTbeta. J. Biol. Chem. 278: 27473-27482.
Wang, W., D.J. Seward, L. Li, J.L. Boyer, and N. Ballatori. (2001). Expression cloning of two genes that together mediate organic solute and steroid transport in the liver of a marine vertebrate. Proc. Natl. Acad. Sci. USA 98: 9431-9436.
Examples:

TC#NameOrganismal TypeExample
2.A.82.1.1

The organic solute transporter, OSTα/OSTβ, which transports steroids and other organic solutes including taurocholate, estrone sulfate, digoxin, and prostaglandin E2 (Wang et al. 2001). Transport is sodium-independent, saturable, and inhibited by other steroids and anionic drugs. Human and mouse OSTalpha-OSTbeta were able to mediate transport of taurocholate, digoxin, and prostaglandin E2 but not of estradiol 17beta-d-glucuronide or p-aminohippurate (Seward et al. 2003).

Animals

OSTα/OSTβ of the little skate, Raja erinacea
OSTα (AAK14805)
OSTβ (AAK14806)

 
2.A.82.1.10

Sdmg1 (TMEM184a) of 425 aas and 7 or 8 TMSs in a 3 or 4 + 4 TMS arrangement. Sdmg1 is a component of secretory granules in mouse secretory exocrine tissues. It is mainly expressed in the gonads where it may have a role in mediating signaling between somatic cells and germ cells. Secretory exocrine cells in the pancreas, salivary gland, and mammary gland also have Sdmg1. Expression is up-regulated during pancreas development when regulated secretory granules start to appear, and Sdmg1 colocalizes with secretory granule markers in adult pancreatic acinar cells. It co-purifies with secretory granules during subcellular fractionation of the pancreas, but Sdmg1 and the secretory granule marker Vamp2 are localized to distinct subdomains in the secretory granule membrane. Thus, Sdmg1 is a component of regulated secretory granules in exocrine secretory cells and the developmental regulation of Sdmg1 expression is related to post-Golgi membrane trafficking (Best and Adams 2009). It is associated with germ cell sex determination and germline-soma interactions in mice (Best et al. 2008).

Sdmg1 of Mus musculus

 
2.A.82.1.11

Lazarus 1 (ZmLAZ1-4) of 404 aas and 7 TMSs. This zinc uptake transporter modulates zinc homeostasis and can be found on plasma and vacuolar membranes in maize (Liu et al. 2022). In plants, it is a Zn2+ transporter in spite of the dissimilar functions of its homologs in animals (Liu et al. 2022).

LAZ1-4 of Zea mays (Maize)

 
2.A.82.1.2

The organic solute transporter OSTα/OSTβ or SLC51A/SLC51B (transports the same anions as the 2.A.82.1.1 system) (The ileal enterocyte basolateral bile acid transporter; uses facilitated diffusion vian an anion:anion antiport mechanism with sulfate or bicarbonate as the counter anion) (Dawson et al., 2005).  Transports steroid-derived molecules as well as glycine and taurine conjugated bile acids (Ballatori et al. 2013).  Heterodimerization increases stability, facilitates post-translational modification and is required for delivery to the plasma membrane.  This system is essential for intestinal bile acid and dietary lipid absorption (Ballatori et al. 2013). Four OSTalpha amino acids (Ser228, Thr229, Gln269 and Glu305) affect expression of OSTalpha/beta and may influence OSTalpha/beta-mediated bile acid transport (Murphy et al. 2021).

Animals

OSTα/OSTβ of Homo sapiens
OSTα (AAP23993)
OSTβ (AAP23992)

 
2.A.82.1.3

Transmembrane protein 184B (Putative MAPK-activating protein FM08).  It has been concluded that this protein is responsible for ibuprofin and possibly taurine uptake, and that its gene expression is regulated by the Nfat5 transcription factor (Rasmussen et al. 2019).

Animals

TMEM184B of Homo sapiens

 
2.A.82.1.4Organic solute transporter alpha-like protein C18A3.4WormC18A3.4 of Caenorhabditis elegans
 
2.A.82.1.5

Ostα subunit homologue

Stramenophiles

Ostα of Thalassiosira oceanica

 
2.A.82.1.6

Uncharacterized protein of 335 aas and 7 TMSs.

UP of Oreochromis niloticus (Nile tilapia) (Tilapia nilotica)

 
2.A.82.1.7

Uncharacteerized protein of 356 aas and 8 TMSs.

UP of Entamoeba histolytica

 
2.A.82.1.8

Transmembrane protein 184 (TMM184) homolog of 426 aas and 6 TMSs.

TMM184 of Schizosaccharomyces pombe (Fission yeast)

 
2.A.82.1.9

TMEM184A of 413 aas and 7 TMSs. Heparin decreases the tumor necrosis factor alpha (TNFalpha)-induced endothelial stress responses in vascular smooth muscle cells, and these responses require transmembrane protein 184A as well as induction of dual specificity phosphatase 1 (Farwell et al. 2016). Thus, TMEM184A functions as a heparin receptor and mediates anti-inflammatory responses.

TMEM184A of Homo sapiens