Abstract
The apical sodium-dependent bile acid transporter (ASBT) utilizes the Na+ concentration gradient to transport bile acids into cells. ASBT is essential in cholesterol homeostasis and blocking of ASBT reduces cholesterol concentration in plasma. A recent structure of a bacterial homolog of ASBT in an inward-open state advanced our understanding of the transporter, but a single conformation does not resolve fundamental questions about the transport mechanism. Here we present crystal structures of an ASBT homolog from Yersinia frederiksenii, ASBTYf in a lipid environment, in an inward-open state at 1.9 A and an outward-open state at 2.5 A. The structures reveal how bile acids could be transported across the membrane by a large rigid-body rotation of a six-helix domain, suggest the existence of a substrate binding site critical for translocation, and show how Na+ could be released into the cytosol. These results build a structural framework for understanding the mechanism of bile acid recognition and transport in ASBT.
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