2.A.28 The Bile Acid:Na+ Symporter (BASS) Family

Functionally characterized members of the BASS family catalyze Na :bile acid symport. These systems have been identified in intestinal, liver and kidney tissues of animals, and at least three isoforms are present in a single species such as humans. The BASS family is also called the Solute Carrier Family 10 (Claro da Silva et al. 2013).

A BASS in the apical membrane of the human ileal intestine catalyzes the electrogenic uptake of bile acids with a stoichiometry of bile acid:Na of 1:2. This protein is associated with the 16 kDa subunit c of the vacuolar proton pump (Sun et al., 2004). This may account for its apical location. Thus, the vacuolar proton pump associated apical sorting machinery may be used to sort the apical Na :bile symporter.

Proteins of the BASS family vary in size from about 340 to 480 amino acyl residues and possess 7 to 10 putative transmembrane spanners (TMSs). The bile acid binding site appears to be localized to the last TMS (last 60 residues) (Kramer et al., 2001). The BASS family belongs to the BART superfamily (Mansour et al., 2007)

These symporters exhibit broad specificity, taking up a variety of non bile organic compounds as well as taurocholate and other bile salts. Homologues are found in plants, yeast, archaea and bacteria. For example, functionally uncharacterized homologues are present in Synechocystis (292 aas; gbD90911) and Bacillus subtilis (283 aas; spP55190; Z99104). The bacterial homologues exhibit 6-10 putative TMSs. Because the family is represented in widely divergent organisms, it is probably ubiquitous.

The rat liver Na /taurocholate cotransporter is subject to elaborate regulation in response to cyclic AMP and cell swelling (McConkey et al., 2004; Webster et al., 2000). It has two N-terminal, N-linked carbohydrate sites and two Tyr-based basolateral sorting motifs at its carboxyl terminus (YEKI and YKAA). The former targets the protein to the apical membrane in the absence of the latter, but the latter overrides the former, targeting the protein to the basolateral membrane (Sun et al., 2001). The ileal homologue has a 14-residue cytoplasmic tail with a β-turn structure that targets the protein to the apical membrane (Sun et al., 2003).

The human orthologue of the rat Na taurocholate symporter (TC #2.A.28.1.1) (NTCP; SLC10A1) exhibits multiple single nucleotide polymorphisms in populations of European, African, Chinese and Hispanic people (Ho et al., 2004). Four nonsynonymous single nucleotide polymorphisms are associated with significant loss of transport function or change in substrate specificity. One form, found in Chinese Americans does not catalyze bile acid uptake but is normal for estrone sulfate uptake. This transporter is responsible for maintenance of enterohepatic recirculation of bile acids (Ho et al., 2004).

High cholesterol levels greatly increase the risk of cardiovascular disease. About 50 per cent of cholesterol is eliminated from the body by its conversion into bile acids. However, bile acids released from the bile duct are constantly recycled, being reabsorbed in the intestine by the apical sodium-dependent bile acid transporter (ASBT, also known as SLC10A2). It has been shown that plasma cholesterol levels are considerably lowered by specific inhibitors of ASBT. Hu et al. (2011) reported the crystal structure of a bacterial homologue of ASBT from Neisseria meningitidis (ASBT(NM)) at 2.2 Å (3ZUY). ASBT(NM) contains two inverted structural repeats of five transmembrane helices. A core domain of six helices harbours two sodium ions, and the remaining four helices pack in a row to form a flat, 'panel'-like domain. Overall, the architecture of the protein is similar to that of the sodium/proton antiporter NhaA. The ASBT(NM) structure was captured with the substrate taurocholate present, bound between the core and panel domains in a large, inward-facing, hydrophobic cavity. Residues near this cavity have been shown to affect the binding of specific inhibitors of human ASBT.

The SLC10 family includes seven genes containing 1-12 exons that encode proteins in humans with sequence lengths of 348-477 amino acids (Döring et al. 2012). Only three out of seven (i.e. SLC10A1, SLC10A2, and SLC10A6) show sodium-dependent uptake of organic substrates across the cell membrane. These include the uptake of bile salts, sulfated steroids, sulfated thyroidal hormones, and certain statin drugs by SLC10A1 (Na+-taurocholate cotransporting polypeptide (NTCP; TC# 2..A.28.1.9)), the uptake of bile salts by SLC10A2 (apical sodium-dependent bile acid transporter (ASBT; TC#2.A.28.1.2)), and uptake of sulfated steroids and sulfated taurolithocholate by SLC10A6 (sodium-dependent organic anion transporter (SOAT; TC# 2.A.28.1.4)). Other members of the family are orphan carriers not all localized in the cell membrane. NTCP and ASBT are carriers for bile salts that establish their enterohepatic circulation. Information is available concerning their 2D and 3D membrane topologies, structure-transport relationships, and ligand and sodium-binding sites. The putative 3D structures have been deduced from the crystal structure of a bacterial homolog, ASBT(NM) (Döring et al. 2012). Knowledge about bile acid synthesis, bile acid hormonal functions, and individual members of the family in terms of expression, localization, substrate pattern, and protein topologies with emphasis on the three functional SLC10 carrier members is presented by (Döring et al. 2012).

The generalized transport reaction catalyzed by members of the BASS family is:

organic acid (out) + Na+ (out) → organic acid (in) + Na+ (in)



This family belongs to the BART Superfamily.

 

References:

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Geyer J., J.R. Godoy, E. Petzinger. (2004). Identification of a sodium-dependent organic anion transporter from rat adrenal gland. Biochem. Biophys. Res. Commun. 316: 300-306.

Geyer, J., C.F. Fernandes, B. Döring, S. Burger, J.R. Godoy, S. Rafalzik, T. Hübschle, R. Gerstberger, and E. Petzinger. (2008). Cloning and molecular characterization of the orphan carrier protein Slc10a4: expression in cholinergic neurons of the rat central nervous system. Neuroscience 152: 990-1005.

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González, P.M., N. Hussainzada, P.W. Swaan, A.D. Mackerell, Jr, and J.E. Polli. (2012). Putative irreversible inhibitors of the human sodium-dependent bile acid transporter (hASBT; SLC10A2) support the role of transmembrane domain 7 in substrate binding/translocation. Pharm Res 29: 1821-1831.

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Hu, N.J., S. Iwata, A.D. Cameron, and D. Drew. (2011). Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT. Nature 478: 408-411.

Khantwal, C.M. and P.W. Swaan. (2008). Cytosolic half of transmembrane domain IV of the human bile acid transporter hASBT (SLC10A2) forms part of the substrate translocation pathway. Biochemistry 47: 3606-3614.

Kramer, W., F. Girbig, H. Glombik, D. Corsiero, S. Stengelin, and C. Weyland. (2001). Identification of a ligand-binding site in the Na+/bile acid cotransporting protein from rabbit ileum. J. Biol. Chem. 276: 36020-36027.

Larhammar, M., K. Patra, M. Blunder, L. Emilsson, C. Peuckert, E. Arvidsson, D. Rönnlund, J. Preobraschenski, C. Birgner, C. Limbach, J. Widengren, H. Blom, R. Jahn, &.#.1.9.7.;. Wallén-Mackenzie, and K. Kullander. (2015). SLC10A4 is a vesicular amine-associated transporter modulating dopamine homeostasis. Biol Psychiatry 77: 526-536.

Mareninova, O., J.M. Shin, O. Vagin, S. Turdikulova, S. Hallen, and G. Sachs. (2005). Topography of the membrane domain of the liver Na+-dependent bile acid transporter. Biochemistry 44: 13702-13712.

Margolles, A., J.A. Moreno, D. van Sinderen, and C.G. de Los Reyes-Gavilán. (2005). Macrolide resistance mediated by a Bifidobacterium breve membrane protein. Antimicrob. Agents Chemother. 49: 4379-4381.

McConkey, M., H. Gillin, C.R.L. Webster, and M.S. Anwer. (2004). Cross-talk between protein kinases Cζ and B in cyclic AMP-mediated sodium taurocholate co-transporting polypeptide translocation in hepatocytes. J. Biol. Chem. 279: 20882-20888.

Melief, E.J., J.T. Gibbs, X. Li, R.G. Morgan, C.D. Keene, T.J. Montine, R.D. Palmiter, and M. Darvas. (2016). Characterization of cognitive impairments and neurotransmitter changes in a novel transgenic mouse lacking Slc10a4. Neuroscience 324: 399-406.

Muthusamy S., Malhotra P., Hosameddin M., Dudeja AK., Borthakur S., Saksena S., Gill RK., Dudeja PK. and Alrefai WA. (2015). N-glycosylation is essential for ileal ASBT function and protection against proteases. Am J Physiol Cell Physiol. 308(12):C964-71.

Patra, K., D.J. Lyons, P. Bauer, M.M. Hilscher, S. Sharma, R.N. Leão, and K. Kullander. (2015). A role for solute carrier family 10 member 4, or vesicular aminergic-associated transporter, in structural remodelling and transmitter release at the mouse neuromuscular junction. Eur J. Neurosci. 41: 316-327.

Rabus, R., D.L. Jack, D.J. Kelly and M.H. Saier, Jr. (1999). TRAP transporters: an ancient family of extracytoplasmic solute-receptor-dependent secondary active transporters. Microbiology 145: 3431-3445.

Rao, A., J. Haywood, A.L. Craddock, M.G. Belinsky, G.D. Kruh, and P.A. Dawson. (2008). The organic solute transporter α-beta, Ostα-Ostbeta, is essential for intestinal bile acid transport and homeostasis. Proc. Natl. Acad. Sci. USA 105: 3891-3896.

Reizer, J., A. Reizer and M.H. Saier, Jr. (1994). A functional superfamily of sodium/solute symporters. Biochim. Biophys. Acta 1197: 133-166.

Russell, D.W. (1999). Nuclear orphan receptors control cholesterol catabolism. Cell 97: 539-542.

Sabit H., Mallajosyula SS., MacKerell AD Jr. and Swaan PW. (2013). Transmembrane domain II of the human bile acid transporter SLC10A2 coordinates sodium translocation. J Biol Chem. 288(45):32394-404.

Saier, M.H., Jr., B.H. Eng, S. Fard, J. Garg, D.A. Haggerty, W.J. Hutchinson, D.L. Jack, E.C. Lai, H.J. Liu, D.P. Nusinew, A.M. Omar, S.S. Pao, I.T. Paulsen, J.A. Quan, M. Sliwinski, T.-T. Tseng, S. Wachi, and G.B. Young. (1999). Phylogenetic characterization of novel transport protein families revealed by genome analyses. Biochim. Biophys. Acta 1422: 1-56.

Slijepcevic, D. and S.F. van de Graaf. (2017). Bile Acid Uptake Transporters as Targets for Therapy. Dig Dis 35: 251-258.

Sun, A.-Q., M.A. Arrese, L. Zeng, I. Swaby, M.-M. Zhou, and F.J. Suchy. (2001). The rat liver Na+/bile acid cotransporter: importance of the cytoplasmic tail to funtion and plasma membrane targeting. J. Biol. Chem. 276: 6825-6833.

Sun, A.-Q., N. Balasubramaniyan, C.-J. Liu, M. Shahid, and F.J. Suchy. (2004). Association of the 16-kDa subunit c of vacuolar proton pump with the ileal Na+-dependent bile acid transporter. Protein-protein interaction and intracellular trafficking. J. Biol. Chem. 279: 16295-16300.

Sun, A.-Q., R. Salkar, Sachchidanand, S. Xu, L. Zeng, M.-M. Zhou, and F.J. Suchy. (2003). A 14-amino acid sequence with a β-turn structure is required for apical membrane sorting of the rat ileal bile acid transporter. J. Biol. Chem. 278: 4000-4009.

Sun, A.Q., N. Balasubramaniyan, H. Chen, M. Shahid, and F.J. Suchy. (2006). Identification of functionally relevant residues of the rat ileal apical sodium-dependent bile acid cotransporter. J. Biol. Chem. 281: 16410-16418.

van der Mark, V.A., D.R. de Waart, K.S. Ho-Mok, M.M. Tabbers, H.W. Voogt, R.P. Oude Elferink, A.S. Knisely, and C.C. Paulusma. (2014). The lipid flippase heterodimer ATP8B1-CDC50A is essential for surface expression of the apical sodium-dependent bile acid transporter (SLC10A2/ASBT) in intestinal Caco-2 cells. Biochim. Biophys. Acta. 1842: 2378-2386.

Wawrzycka, D., K. Markowska, E. Maciaszczyk-Dziubinska, M. Migocka, and R. Wysocki. (2016). Transmembrane topology of the arsenite permease Acr3 from Saccharomyces cerevisiae. Biochim. Biophys. Acta. 1859: 117-125. [Epub: Ahead of Print]

Webster, C.R., C.J. Blanch, J. Phillips, and M.S. Anwer. (2000). Cell swelling-induced translocation of rat liver Na+/taurocholate cotransport polypeptide is mediated via the phosphoinositide 3-kinase signaling pathway. J. Biol. Chem. 275: 29754-29760.

Weinman, S.A., M.W. Carruth, and P.A. Dawson. (1998). Bile acid uptake via the human apical sodium-bile acid cotransporter is electrogenic. J. Biol. Chem. 273: 34691-34695.

Yan, H., G. Zhong, G. Xu, W. He, Z. Jing, Z. Gao, Y. Huang, Y. Qi, B. Peng, H. Wang, L. Fu, M. Song, P. Chen, W. Gao, B. Ren, Y. Sun, T. Cai, X. Feng, J. Sui, and W. Li. (2012). Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. elife 1: e00049.

Zhang J., Fu LL., Tian M., Liu HQ., Li JJ., Li Y., He J., Huang J., Ouyang L., Gao HY. and Wang JH. (2015). Design and synthesis of a novel candidate compound NTI-007 targeting sodium taurocholate cotransporting polypeptide [NTCP]-APOA1-HBx-Beclin1-mediated autophagic pathway in HBV therapy. Bioorg Med Chem. 23(5):976-84.

Zhao, Y., X. Ai, M. Wang, L. Xiao, and G. Xia. (2016). A putative pyruvate transporter TaBASS2 positively regulates salinity tolerance in wheat via modulation of ABI4 expression. BMC Plant Biol 16: 109.

Zhou, X., E.J. Levin, Y. Pan, J.G. McCoy, R. Sharma, B. Kloss, R. Bruni, M. Quick, and M. Zhou. (2014). Structural basis of the alternating-access mechanism in a bile acid transporter. Nature 505: 569-573.

Examples:

TC#NameOrganismal TypeExample
2.A.28.1.1Organic acid/(conjugated) bile acid (taurocholate):Na+ symporter. Taurine conjugates > glycine conjugates > unconjugated bile salts. Animals Liver bile acid uptake system of Rattus norvegicus
 
2.A.28.1.10

BASS family homologue

Proteobacteria

BASS family homologue of Myxococcus xanthus

 
2.A.28.1.2

Liver/ileal bile acid:Na+ symporter, ASBT, ISBT or NTCP2 (SLC10A2) of 348 aas and 7 TMSs (Mareninova et al. 2005) (essential for liver or intestinal bile acid transport and homeostasis (Rao et al., 2008). TMS4 forms part of the substrate translocation pathway (Khantwal and Swaan, 2008); TMS7 plays a role in substrate binding and translocation (González et al., 2012); TMS1 contributes to substrate translocation and protein stability (da Silva et al., 2011), and TMS2 coordinates Na+ translocation (Sabit et al. 2013).  NTCP serves as the Hepatitis B Virus (HBV) receptor, and drugs developed to target NTCP induce autophagy and may provide therapy for HBV (Zhang et al. 2015). Decreased activity leads to luminal bile salt concentrations and either increased eletrolyte secretion or decreased reabsolption (van der Mark et al., 2014). Function and stability depend on N-glycosylation (Muthusamy et al. 2015).  Specific inhibitors are known (Slijepcevic and van de Graaf 2017). It has a 7 TMS topology (Banerjee and Swaan 2006). Chronic hepatitis B, C and D viruses (HBV, HCV and HDV) infect the liver and cause cancer. The three viruses are exclusively hepatotropic, and NTCP mediates the transport of bile acids and plays a key role in HBV HCV and HDV entry into hepatocytes. It modulates HCV infection by regulating innate antiviral immune responses in the liver (Eller et al. 2018).

Animals

NTCP of Homo sapiens

 
2.A.28.1.3The organic anion:Na+ symporter, SOAT (transports estrone-3-sulfate (Km= 31 μM) and dehydropiandrosterone sulfate (Km = 30 μM) but not taurocholate, estradiol-17β-glucuronide or ouabain) (Geyer et al., 2004)AnimalsSOAT of Rattus norvegicus
(Q70EX6)
 
2.A.28.1.4The organic anion:Na+ symporter, SOAT (probable paralogue of 2.A.28.1.3); a 7 TMS protein with the N-terminus out and the C-terminus in. Transports dehydroepiandrosterone sulfate, estrone-3-sulfate, and pregnenolone sulfate with Km values of 30, 12 and 11 μM, respectively. Sulfoconjugated taurolithocholate is also a substrate. Cholate, taurocholate and chenodeoxycholate are not substrates. (Geyer et al., 2007). AnimalsSLC10A6 of Homo sapiens
 
2.A.28.1.5

solute carrier family 10 (sodium/bile acid cotransporter family), member 3

Animals

SLC10-3 of Bos taurus (Q0V8N6)

 
2.A.28.1.6

solute carrier family 10 (sodium/bile acid cotransporter family), member 5

AnimalsSLC10A5 of Homo sapiens
 
2.A.28.1.7

Solute carrier family 10 (sodium/bile acid cotransporter family), member 4.  The rat orthologue is found in cholinergic neurons of the brain together with the vesicular acetyl choline transporter, VAChT (TC# 2.A.1.2.28), and the high affinity choline transporter, CHT1 (TC#s 2.A.21.8.1 & 2) (Geyer et al. 2008).  It is a protease-activated bile acid transporter (Abe et al. 2013).  It has also been reported to be a vesicular monoaminergic and cholinergic associated transporter that is important for dopamine homeostasis and neuromodulation in vivo, and it may play a role in neurotransmitter release at the neuromuscular junction (Larhammar et al. 2015; Patra et al. 2015). It's loss in mice results in cognitive impairment (Melief et al. 2016).

Animals

SLC10A4 of Homo sapiens

 
2.A.28.1.8P3 protein (Solute carrier family 10 member 3)AnimalsSLC10A3 of Homo sapiens
 
2.A.28.1.9

Sodium/bile acid cotransporter (Cell growth-inhibiting gene 29 protein; Na+/bile acid cotransporter; Na+/taurocholate transport protein; NTCP; Solute carrier family 10 member 1). Transports steroids and xenobiotics, including HMG-CoA reductase inhibiitors (statins). This protein is the hepatitis B and D virus receptor (Yan et al. 2012). Specific inhibitors are known (Slijepcevic and van de Graaf 2017).

Animals

SLC10A1 of Homo sapiens

 
Examples:

TC#NameOrganismal TypeExample
2.A.28.2.1

The chloroplastic glucosinolate uptake porter, BAT5 (Gigolashvili et al., 2009) [glucosinolates are thioglucosides of amino acid derivatives. These bitter natural pesticides are present in most plants of the order Brassicales among others].

Plants

BAT5 of Arabidopsis thaliana (Q3EA49)

 
2.A.28.2.2

Chloroplast envelope membrane pyruvate:Na+ symporter, called Bile acid:sodium symporter, protein 2, BASS2 (widely distributed in all land plants tested) (Furumoto et al., 2011).

Plants

BASS2 of Flaveria trinervia (E0D3H5)

 
2.A.28.2.3

Chloroplast envelope membrane pyruvate:Na+ symporter, BASS2. (Orthologous to 2.A.28.2.2) (Furumoto et al., 2011; Furumoto 2016). The wheat ortholog functions in salt tolerance (Zhao et al. 2016).

Plants

BASS2 pf Arabidopsis thaliana (Q1EBV7)

 
2.A.28.2.4

Na+:bile acid symporter (AstB). The 3-d structure is available (3ZUX).

Bacteria

AstB of Neisseria meningitidis (Q9K0A9)

 
2.A.28.2.5

Putative Na+ symporter

Bacteria

YqcL of Paenibacillus sp. JDR-2 (C6CWW0)

 
2.A.28.2.6

Probable macrolide resistance porter (very similar to the orthologue in B. brevis) (Margolles et al. 2005).

Actinobacteria

Macrolide resistance protein of Bifidobacterium longum

 
2.A.28.2.7

Putative Na+ symporter (10 TMSs)

Archaea

Putative Na+ symporter of Halomicrobium mukohataei (C7NY93)

 
2.A.28.2.8

Putative integral membrane protein

Actinobacteria

 
2.A.28.2.9

Sodium bile acid symporter family protein, ASBT, of 307 aas and 10 TMSs.  The 3-d structure has been solved (4N7W) (Zhou et al. 2014). This structure has been used to model the yeast Acr3  protein (TC# 2.A.59.1.1) which is in a distinct family of the BART superfamily (Wawrzycka et al. 2016).

ASBT of Yersinia frederiksenii

 
Examples:

TC#NameOrganismal TypeExample
2.A.28.3.1

Solute carrier family 10, member 7 protein (358 aas; 10 established TMSs with the N- and C-termini in the cytoplasm (Godoy et al. 2007)) (Zou et al., 2005).  Present in the plasma membrane.  Slc10a7 KO mice exhibit moderate skeletal dysplasia (osteochondrodyplasia), characterized by markedly shortened and mildly bowed limbs (Brommage et al. 2014). SLC10A7 plays roles in glycosaminoglycan synthesis and skeletal development, and mutants in its gene can cause skeletal dysplasia in mice and humans (Dubail et al. 2018). It plays a role in bone mineralization and transport of glycoproteins to the extracellular matrix (Ashikov et al. 2018).

Animals

SLC10A7 of Homo sapiens

 
2.A.28.3.2Putative Na+-dependent transporterPlantsPutative transporter of Arabidopsis thaliana (Q9LYM5)
 
2.A.28.3.3

Putative Na+-dependent transporter

Bacteria

Putative transporter of Paracoccus denitrificans

 
2.A.28.3.4Putative Na+-dependent transporter, YfeH (332 aas; 7-10 TMSs)BacteriaYfeH of E. coli (P39836)
 
2.A.28.3.5Putative Na+-dependent transporter (322 aas; 8-10 TMSs)BacteriaTransporter of Lentisphaera araneosa (A6DUG7)
 
2.A.28.3.6

Fusion Protein of 928aas: N-terminal Cysteine proteinase/Cathepsin F (residues 1-578/Peptidase CIA family) C-terminal BART sugar family domain (579-928).

Plants

Protease/transporter fusion protein of Ostreococcus tauri (Q01E11)

 
2.A.28.3.7

RCh1p transporter (SLC10 family). Regulates cytosolic Ca2+ homeostasis (Jiang et al., 2012).  Rch1p is part of the low-affinity calcium uptake system (LACS) system and does not functionally interact with Cch1p (Alber et al. 2013).

Yeast

RCh1p of Candida albicans (Q59UQ7)

 
Examples:

TC#NameOrganismal TypeExample
2.A.28.4.1

Uncharacterized protein of 360 aas with an N-terminal hydrophobic domain of 4 - 5 TMSs homologous to members of this family.  The C-terminal hydrophilic domain may be related to TC# 1.C.96, and 1.C.96 may be related to 1.C.5 in the aerolysin superfamily.

UP of Crassostrea gigas (Pacific oyster) (Crassostrea angulata)