Methylation-regulated decommissioning of multimeric PP2A complexes

Cheng-Guo Wu, Aiping Zheng, Li Jiang, Michael Rowse, Vitali Stanevich, Hui Chen, Yitong Li, Kenneth A. Satyshur, Benjamin Johnson, Ting-Jia Gu, Zuojia Liu and Yongna Xing ()
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Cheng-Guo Wu: School of Medicine and Public Health
Aiping Zheng: School of Medicine and Public Health
Li Jiang: School of Medicine and Public Health
Michael Rowse: School of Medicine and Public Health
Vitali Stanevich: School of Medicine and Public Health
Hui Chen: School of Medicine and Public Health
Yitong Li: School of Medicine and Public Health
Kenneth A. Satyshur: School of Medicine and Public Health
Benjamin Johnson: School of Medicine and Public Health
Ting-Jia Gu: School of Medicine and Public Health
Zuojia Liu: School of Medicine and Public Health
Yongna Xing: School of Medicine and Public Health

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Dynamic assembly/disassembly of signaling complexes are crucial for cellular functions. Specialized latency and activation chaperones control the biogenesis of protein phosphatase 2A (PP2A) holoenzymes that contain a common scaffold and catalytic subunits and a variable regulatory subunit. Here we show that the butterfly-shaped TIPRL (TOR signaling pathway regulator) makes highly integrative multibranching contacts with the PP2A catalytic subunit, selective for the unmethylated tail and perturbing/inactivating the phosphatase active site. TIPRL also makes unusual wobble contacts with the scaffold subunit, allowing TIPRL, but not the overlapping regulatory subunits, to tolerate disease-associated PP2A mutations, resulting in reduced holoenzyme assembly and enhanced inactivation of mutant PP2A. Strikingly, TIPRL and the latency chaperone, α4, coordinate to disassemble active holoenzymes into latent PP2A, strictly controlled by methylation. Our study reveals a mechanism for methylation-responsive inactivation and holoenzyme disassembly, illustrating the complexity of regulation/signaling, dynamic complex disassembly, and disease mutations in cancer and intellectual disability.

Date: 2017
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DOI: 10.1038/s41467-017-02405-3

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