Modulation of nongenomic activation of PI3K signalling by tetramerization of N-terminally-cleaved RXRα

Liqun Chen, Alexander E. Aleshin, Gulimiran Alitongbieke, Yuqi Zhou, Xindao Zhang, Xiaohong Ye, Mengjie Hu, Gaoang Ren, Ziwen Chen, Yue Ma, Duo Zhang, Shuai Liu, Weiwei Gao, Lijun Cai, Lingjuan Wu, Zhiping Zeng, Fuquan Jiang, Jie Liu, Hu Zhou, Gregory Cadwell, Robert C. Liddington, Ying Su () and Xiao-kun Zhang ()
Additional contact information
Liqun Chen: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Alexander E. Aleshin: Sanford Burnham Prebys Medical Discovery Institute
Gulimiran Alitongbieke: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Yuqi Zhou: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Xindao Zhang: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Xiaohong Ye: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Mengjie Hu: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Gaoang Ren: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Ziwen Chen: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Yue Ma: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Duo Zhang: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Shuai Liu: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Weiwei Gao: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Lijun Cai: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Lingjuan Wu: College of Biological Science and Engineering, Fuzhou University
Zhiping Zeng: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Fuquan Jiang: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Jie Liu: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Hu Zhou: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Gregory Cadwell: Sanford Burnham Prebys Medical Discovery Institute
Robert C. Liddington: Sanford Burnham Prebys Medical Discovery Institute
Ying Su: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University
Xiao-kun Zhang: School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: Abstract Retinoid X receptor-alpha (RXRα) binds to DNA either as homodimers or heterodimers, but it also forms homotetramers whose function is poorly defined. We previously discovered that an N-terminally-cleaved form of RXRα (tRXRα), produced in tumour cells, activates phosphoinositide 3-kinase (PI3K) signalling by binding to the p85α subunit of PI3K and that K-80003, an anti-cancer agent, inhibits this process. Here, we report through crystallographic and biochemical studies that K-80003 binds to and stabilizes tRXRα tetramers via a ‘three-pronged’ combination of canonical and non-canonical mechanisms. K-80003 binding has no effect on tetramerization of RXRα, owing to the head–tail interaction that is absent in tRXRα. We also identify an LxxLL motif in p85α, which binds to the coactivator-binding groove on tRXRα and dissociates from tRXRα upon tRXRα tetramerization. These results identify conformational selection as the mechanism for inhibiting the nongenomic action of tRXRα and provide molecular insights into the development of RXRα cancer therapeutics.

Date: 2017
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DOI: 10.1038/ncomms16066

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