skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Methylation-regulated decommissioning of multimeric PP2A complexes

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.

Authors:
; ORCiD logo; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1418027
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Communications; Journal Volume: 8; Journal Issue: 1
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Wu, Cheng-Guo, Zheng, Aiping, Jiang, Li, Rowse, Michael, Stanevich, Vitali, Chen, Hui, Li, Yitong, Satyshur, Kenneth A., Johnson, Benjamin, Gu, Ting-Jia, Liu, Zuojia, and Xing, Yongna. Methylation-regulated decommissioning of multimeric PP2A complexes. United States: N. p., 2017. Web. doi:10.1038/s41467-017-02405-3.
Wu, Cheng-Guo, Zheng, Aiping, Jiang, Li, Rowse, Michael, Stanevich, Vitali, Chen, Hui, Li, Yitong, Satyshur, Kenneth A., Johnson, Benjamin, Gu, Ting-Jia, Liu, Zuojia, & Xing, Yongna. Methylation-regulated decommissioning of multimeric PP2A complexes. United States. doi:10.1038/s41467-017-02405-3.
Wu, Cheng-Guo, Zheng, Aiping, Jiang, Li, Rowse, Michael, Stanevich, Vitali, Chen, Hui, Li, Yitong, Satyshur, Kenneth A., Johnson, Benjamin, Gu, Ting-Jia, Liu, Zuojia, and Xing, Yongna. Fri . "Methylation-regulated decommissioning of multimeric PP2A complexes". United States. doi:10.1038/s41467-017-02405-3.
@article{osti_1418027,
title = {Methylation-regulated decommissioning of multimeric PP2A complexes},
author = {Wu, Cheng-Guo and Zheng, Aiping and Jiang, Li and Rowse, Michael and Stanevich, Vitali and Chen, Hui and Li, Yitong and Satyshur, Kenneth A. and Johnson, Benjamin and Gu, Ting-Jia and Liu, Zuojia and Xing, Yongna},
abstractNote = {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.},
doi = {10.1038/s41467-017-02405-3},
journal = {Nature Communications},
number = 1,
volume = 8,
place = {United States},
year = {Fri Dec 01 00:00:00 EST 2017},
month = {Fri Dec 01 00:00:00 EST 2017}
}