College of Life Sciences, South China Agricultural University, Guangzhou, China.
College of Life Sciences, South China Agricultural University, Guangzhou, China; Guangdong Provincial Key Laboratory of Protein Function and Regulation in Agricultural Organisms, South China Agricultural University, Guangzhou, China.
Biochim Biophys Acta Biomembr. 2021 Apr 1;1863(4):183554. doi: 10.1016/j.bbamem.2021.183554. Epub 2021 Jan 8.
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.
有机阴离子转运多肽（OATPs）是负责摄取广泛的内源性化合物和临床重要药物的跨膜蛋白。肝脏特异性 OATP1B1 在去除许多口服药物方面起着至关重要的作用。因此，转运体的正常功能对于各种治疗剂的药代动力学至关重要。膜蛋白往往形成寡聚体，这对于它们的稳定性、靶向和/或与底物的相互作用很重要。我们实验室的先前研究表明，OATP1B1 可能形成同源寡聚体，并且位于跨膜域 8（TM8）的 GXXXG 基序可能影响其寡聚化。在当前的研究中，研究了 OATP1B1 跨膜域内的三个短形式亮氨酸七肽重复序列。结果发现，TM3 内亮氨酸七肽重复序列的破坏显著降低了 OATP1B1 的摄取功能和蛋白-蛋白相互作用；而在 TM8 中，只有 L378 对 OATP1B1 的功能至关重要，并且 L378 的丙氨酸替换对寡聚化没有影响。TM3 的片段表达干扰了 OATP1B1 同源寡聚体的形成以及与 OATP1B3 的结合，OATP1B3 也选择性地在人肝细胞中表达，这表明该区域可能被两种转运体共享用于其蛋白-蛋白相互作用。
