Structure and Function of a Bacterial Homolog of the SLC10 Family Bile Acid Transporters

The SLC10 family bile acid transporters (BATs) in mammals play critical roles in driving enterohepatic circulation and maintaining bile salt and cholesterol homeostasis by transporting bile acids into cells. For example, the uptake of bile acids from the portal blood into the liver is mediated primarily by the Na+-taurocholate cotransporting polypeptide (NTCP; SLC10A1), whereas in the ileum the apical sodium-dependent bile acid transporter (ASBT; SLC10A2) takes up bile acids from the lumen into the epithelial cells. To understand better the transporting mechanism of BATs, we have crystallized and solved the structure of a bacterial homolog of BAT to a resolution of 3.0 A. The bacterial BAT shares 54% sequence similarity with NTCP and 60% similarity with human ASBT, and many of the NTCP and ASBT residues known to be essential for function are conserved in the bacterial BAT. The overall structural fold of the bacterial BAT unexpectedly resembles that of the Na+-H+ antiporter NhaA, although the bacterial BAT is likely a Na+-dependent bile acid symporter and the two do not have significant sequence similarity. In combination with functional assays to monitor binding and transport of bile acids by the bacterial BAT, the structure suggests possible mechanisms for substrate selectivity and translocation.