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    Identification of Key Amino Acids that Impact Organic Solute Transporter / (OSTα/β).

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    Author
    Murphy, William A
    Beaudoin, James J
    Laitinen, Tuomo
    Sjöstedt, Noora
    Malinen, Melina M
    Ho, Henry
    Swaan, Peter W
    Honkakoski, Paavo
    Brouwer, Kim L R
    Date
    2021-10-01
    Journal
    Molecular Pharmacology
    Publisher
    American Society for Pharmacology and Experimental Therapy
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1124/MOLPHARM.121.000345
    Abstract
    Organic solute transporter α/β (OSTα/β) is a bidirectional bile acid transporter localized on the basolateral membrane of hepatic, intestinal, and renal epithelial cells. OSTα/β plays a critical role in intestinal bile acid reabsorption and is upregulated in hepatic diseases characterized by elevated bile acids, whereas genetic variants in SLC51A/B have been associated with clinical cholestasis. OSTα/β also transports and is inhibited by commonly used medications. However, there is currently no high-resolution structure of OSTα/β, and structure-function data for OSTα, the proposed substrate-binding subunit, are lacking. The present study addressed this knowledge gap and identified amino acids in OSTα that are important for bile acid transport. This was accomplished using computational modeling and site-directed mutagenesis of the OSTα subunit to generate OSTα/β mutant cell lines. Out of the 10 OSTα/β mutants investigated, four (S228K, T229S, Q269E, Q269K) exhibited decreased [3H]-taurocholate (TCA) uptake (ratio of geometric means relative to OSTα/β wild type (WT) of 0.76, 0.75, 0.79, and 0.13, respectively). Three OSTα/β mutants (S228K, Q269K, E305A) had reduced [3H]-TCA efflux % (ratio of geometric means relative to OSTα/β WT of 0.86, 0.65, and 0.79, respectively). Additionally, several OSTα/β mutants demonstrated altered expression and cellular localization when compared with OSTα/β WT. In summary, we identified OSTα residues (Ser228, Thr229, Gln269, Glu305) in predicted transmembrane domains that affect expression of OSTα/β and may influence OSTα/β-mediated bile acid transport. These data advance our understanding of OSTα/β structure/function and can inform future studies designed to gain further insight into OSTα/β structure or to identify additional OSTα/β substrates and inhibitors. SIGNIFICANCE STATEMENT: OSTα/β is a clinically important transporter involved in enterohepatic bile acid recycling with currently no high-resolution protein structure and limited structure-function data. This study identified four OSTα amino acids (Ser228, Thr229, Gln269, Glu305) that affect expression of OSTα/β and may influence OSTα/β-mediated bile acid transport. These data can be utilized to inform future investigation of OSTα/β structure and refine molecular modeling approaches to facilitate the identification of substrates and/or inhibitors of OSTα/β.
    Rights/Terms
    Copyright © 2021 by The American Society for Pharmacology and Experimental Pharmaceutics.
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/17637
    ae974a485f413a2113503eed53cd6c53
    10.1124/molpharm.121.000345
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