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Oligomerization Study of Human Organic Anion Transporting Polypeptide 1B1
Chunxu Ni1, Xuan Yu1, Zihui Fang1
1College of Life Sciences, South China Agricultural University , Guangzhou 541642, China.
Molecular Pharmaceutics
|December 13, 2016
Summary
Organic anion-transporting polypeptide 1B1 (OATP1B1) may form oligomers, influencing substrate uptake. Mutations in specific motifs suggest oligomerization is crucial for high-affinity transport of estrone-3-sulfate (ES).
Area of Science:
- Membrane protein biophysics
- Drug transporter function
- Molecular cell biology
Background:
- Organic anion-transporting polypeptides (OATPs) are crucial for transporting diverse molecules across cell membranes.
- The oligomerization status of OATPs, including OATP1B1, remains largely undetermined.
- Protein oligomerization is a common mechanism regulating membrane transporter activity.
Purpose of the Study:
- To investigate the oligomerization status of OATP1B1.
- To determine the role of OATP1B1 oligomerization in the transport of estrone-3-sulfate (ES).
- To elucidate the function of GXXXG motifs in OATP1B1 oligomerization and transport activity.
Main Methods:
- Stable expression of OATP1B1 in HEK293 cells.
- Chemical cross-linking and coimmunoprecipitation assays to assess oligomerization.
- Site-directed mutagenesis of GXXXG motifs and functional analysis of substrate uptake kinetics.
Main Results:
- OATP1B1 forms homo-oligomers, potentially via disulfide bonds.
- Oligomerization-deficient mutants show reduced ES uptake, particularly affecting high-affinity binding.
- Mutations in GXXXG motifs (G219A, G393A) significantly impair Vmax and alter Km for ES, with G393A impacting oligomerization.
Conclusions:
- OATP1B1 likely functions as oligomers for high-affinity ES binding and transport.
- Monomeric forms of OATP1B1 may mediate low-affinity substrate interactions.
- Specific GXXXG motifs are critical for OATP1B1 oligomerization and efficient substrate translocation.
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