Leucine heptad motifs within transmembrane domains affect function and oligomerization of human organic anion transporting polypeptide 1B1.

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  • Author(s): Ni C;Ni C; Wang X; Wang X; Chen J; Chen J; Xu S; Xu S; Ye W; Ye W; Hong M; Hong M; Hong M
  • Source:
    Biochimica et biophysica acta. Biomembranes [Biochim Biophys Acta Biomembr] 2021 Apr 01; Vol. 1863 (4), pp. 183554. Date of Electronic Publication: 2021 Jan 08.
  • Publication Type:
    Journal Article; Research Support, Non-U.S. Gov't
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101731713 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1879-2642 (Electronic) Linking ISSN: 00052736 NLM ISO Abbreviation: Biochim Biophys Acta Biomembr Subsets: MEDLINE
    • Publication Information:
      Original Publication: Amsterdam : Elsevier
    • Subject Terms:
      Protein Multimerization*; Cell Membrane/*metabolism ; Liver-Specific Organic Anion Transporter 1/*metabolism; Amino Acid Motifs ; Cell Membrane/genetics ; HEK293 Cells ; Humans ; Liver-Specific Organic Anion Transporter 1/genetics ; Protein Domains
    • Abstract:
      Organic anion transporting polypeptides (OATPs) are transmembrane proteins responsible for the uptake of a wide range of endogenous compounds and clinically important drugs. The liver-specific OATP1B1 serves crucial roles in the removal of many orally administered drugs. The proper function of the transporter hence is essential for the pharmacokinetics of various therapeutic agents. Membrane proteins tend to form oligomers that are important for their stability, targeting and/or interactions with the substrates. Previous study in our laboratory revealed that OATP1B1 may form homo-oligomers and that a GXXXG motif localized at transmembrane domain 8 (TM8) may affect its oligomerization. In the current study, three short-form leucine heptad repeats within the transmembrane domains of OATP1B1 were investigated. It was found that the disruption of leucine heptad repeats within TM3 dramatically reduced the uptake function and protein-protein association of OATP1B1; while within TM8, only L378 is essential for the function of OATP1B1 and alanine replacement of L378 exhibited no effect on the oligomerization. The fragmental expression of TM3 interfered with the association of OATP1B1 homo-oligomers as well as its association with OATP1B3, which is also selectively expressed at human hepatocytes, suggesting that the region may be shared by both transporters for their protein-protein interactions.
      (Copyright © 2021 Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Drug transporters; Leucine heptad repeats; Oligomerization; Organic anion transporting polypeptides; Uptake function
    • Accession Number:
      0 (Liver-Specific Organic Anion Transporter 1)
      0 (SLCO1B1 protein, human)
    • Publication Date:
      Date Created: 20210111 Date Completed: 20210629 Latest Revision: 20210629
    • Publication Date:
      20240829
    • Accession Number:
      10.1016/j.bbamem.2021.183554
    • Accession Number:
      33428894