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).This family has been reported to have the NhaA fold (Ferrada and Superti-Furga 2022).

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)