Amino-terminal region of human organic anion transporting polypeptide 1B1 dictates transporter stability and substrate interaction.
Toxicology and applied pharmacology(2019)
Abstract
Organic anion transporting polypeptides (OATPs) are key players of drug absorption, distribution and excretion due to their broad substrate specificity, wide tissue distribution and the involvement in drug-drug interaction. OATP1B1 is specifically localized at the basolateral membrane of human hepatocytes and serves a crucial role in the drug clearance from the body. Previous studies have shown that transmembrane domains (TMs) are essential for proper functions of OATPs. In the present study, site-directed mutagenesis was performed to study the TM1 and amino-terminus of OATP1B1. Two positively charged residues, K41 and K49, as well as a hydrophobic residue I46, in TM1 were identified to be important for the proper function of the transporter. K41A and K49A exhibited altered Km value at the high and low affinity binding sites of estrone-3- sulfate (ES), respectively; while alanine substitution of I46 showed altered Km and Vmax values for both binding components of ES. Additional replacement of K41 revealed that the positively charged property at this position is important for maintaining OATP1B1 protein level and function; while the specific side-group structure of lysine at position 49 is irreplaceable for the transporter activity. Conservative replacement of I46 with leucine also recovered the function of the transporter. In addition, studies of the amino-terminus of OATP1B1 revealed that residues ranging from 19 to 27 are essential for protein stability and substrate interaction. Therefore, the amino-terminal region, which includes TM1 and the amino-terminus of OATP1B1, is important for proper function of the membrane protein.
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