Bile acid is useful in digesting lipids and vitamins. However, there can be too much of a good thing: excessive bile acid may upset metabolism or even cause cancer. Thus, it is necessary for human liver to export excessive bile acid so as to maintain its benign circulation. ABCB11 is an important bile acid transporter, but its transport mechanism remains unclear.
In order to understand the transport mechanism, the research team led by Prof. CHEN Yuxing and Prof. ZHOU Congzhao from University of Science and Technology of China (USTC) of the Chinese Academy of Sciences solved the structures of human ABCB11 under various taurocholate (TC, a kind of bile acid) concentrations and revealed a pocket-to-pocket bile acid transfer mechanism. The results were published in Cell Research .
Researchers discovered two tandem binding sites in ABCB11 that were located in the outer membrane leaflet (OML) and inner membrane leaflet (IML) respectively. The OML pocket and IML pocket have different substrate affinities, and this affinity gradient made ABCB11 a “one-way street” for substrates, enabling the export of bile acid.
The two-pocket structure allowed for more precise recognition of bile acid. Researchers found that the IML pocket had two positively charge residues that served to recognize taurine moiety of bile acid. The OML pocket, on the other hand, served to recognize the cholic acid moiety and the shape of bile acid.
The results of this study not only contribute to our understanding of the mechanism of bile acid transport, but also provide structural basis for therapeutic intervention and drug design of cholestasis and other diseases.
Cell Research
Structures of human bile acid exporter ABCB11 reveal a transport mechanism facilitated by two tandem substrate-binding pockets
18-Jan-2022