Featured Article - September 2014
Short description: Crystal structures of sodium-dependent bile acid transporters provide insight into transport mechanism.
Bile acids are cholesterol-based compounds that solubilize lipids, facilitating the uptake of dietary lipids and fat-soluble vitamins in the intestine. Bile acids are produced in the liver and released into the intestine; once the acids release their lipid cargoes, sodium-dependent bile acid transporters (ASBTs) mediate the cellular re-uptake of bile acids and their subsequent transport back to the liver. Blocking bile acid recycling can lower cholesterol levels, as new bile acids would need to be produced from cellular cholesterol pools. Thus, ASBT is a potential drug target to treat hypercholesterolemia and type 2 diabetes.
Substrate transport across the cellular membrane is thought to occur through an alternating-access mechanism: the transporter core has access to substrate on one side, and substrate binding to the transporter induces a conformational change, leading to a transporter opening on the alternate side and substrate release. A crystal structure of Neisseria meningitidis ASBT bound to two Na+ and taurocholic acid was previously solved in detergent: it captured the transporter in an inward-open conformation and revealed the substrate-binding site. However, definitive structural evidence for an alternating-access mechanism in ASBT was lacking.
Quick, Zhou and colleagues (PSI NYCOMPS) now report structural work on the ASBT homolog from the bacterium Yersinia frederiksenii, crystallized in a lipid environment. The crystal structures of substrate-free wild-type ASBT (PDB 4N7W) and a mutant unable to bind sodium (PDB 4N7X) assume inward- and outward-facing open conformations, respectively.
The structures show a dramatic difference in the relative arrangement of the transporter's panel and core regions. However, a narrow area within the core region containing highly conserved residues remains accessible in both conformations. Unexpectedly, the bile acid- binding site previously identified is only accessible in the inward-facing conformation, supporting an alternate binding site mechanism.
Based on structural and biochemical data, the authors propose that the binding of Na+ to ASBT is required for subsequent attachment of bile acid to the transporter's core, which leads to a conformational change from inward- to outward-facing states. The low sodium levels in the interior of the cell then trigger the release of sodium ions followed by the bile acid substrate.
X. Zhou et al. Structural basis of the alternating-access mechanism in a bile acid transporter.
Nature. 505, 569-573 (2014). doi:10.1038/nature12811