Methylation-regulated decommissioning of multimeric PP2A complexes

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

doi:10.1038/s41467-017-02405-3

Title: Methylation-regulated decommissioning of multimeric PP2A complexes

Journal Article · Fri Dec 01 00:00:00 EST 2017 · Nature Communications

DOI:https://doi.org/10.1038/s41467-017-02405-3· OSTI ID:1418027

Wu, Cheng-Guo;

; Jiang, Li; Rowse, Michael; Stanevich, Vitali; Chen, Hui; Li, Yitong; Satyshur, Kenneth A.; Johnson, Benjamin; Gu, Ting-Jia; Liu, Zuojia; Xing, Yongna

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.

Cite

Export

Save

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC)

OSTI ID:: 1418027

Journal Information:: Nature Communications, Vol. 8, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing Group

Country of Publication:: United States

Language:: ENGLISH

References (56)

Crank Ness, Steven R.; de Graaff, Rudolf A. G.; Abrahams, Jan Pieter Structure, Vol. 12, Issue 10 https://doi.org/10.1016/j.str.2004.07.018	journal	October 2004
From Promiscuity to Precision: Protein Phosphatases Get a Makeover Virshup, David M.; Shenolikar, Shirish Molecular Cell, Vol. 33, Issue 5 https://doi.org/10.1016/j.molcel.2009.02.015	journal	March 2009
Protein phosphatase 2A subunit assembly: the catalytic subunit carboxy terminus is important for binding cellular B subunit but not polyomavirus middle tumor antigen Ogris, Egon; Gibson, Daryl M.; Pallas, David C. Oncogene, Vol. 15, Issue 8 https://doi.org/10.1038/sj.onc.1201259	journal	August 1997
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
Serine/Threonine Phosphatases: Mechanism through Structure Shi, Yigong Cell, Vol. 139, Issue 3 https://doi.org/10.1016/j.cell.2009.10.006	journal	October 2009
Molecular Chaperones in Cellular Protein Folding: The Birth of a Field Horwich, Arthur L. Cell, Vol. 157, Issue 2 https://doi.org/10.1016/j.cell.2014.03.029	journal	April 2014
Spatial control of protein phosphatase 2A (de)methylation Longin, Sari; Zwaenepoel, Karen; Martens, Ellen Experimental Cell Research, Vol. 314, Issue 1 https://doi.org/10.1016/j.yexcr.2007.07.030	journal	January 2008
Iterative model building, structure refinement and density modification with the PHENIX AutoBuild wizard Terwilliger, Thomas C.; Grosse-Kunstleve, Ralf W.; Afonine, Pavel V. Acta Crystallographica Section D Biological Crystallography, Vol. 64, Issue 1 https://doi.org/10.1107/S090744490705024X	journal	December 2007
Leucine Carboxyl Methyltransferase-1 Is Necessary for Normal Progression through Mitosis in Mammalian Cells Lee, Jocelyn A.; Pallas, David C. Journal of Biological Chemistry, Vol. 282, Issue 42 https://doi.org/10.1074/jbc.M704861200	journal	August 2007
Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase Verba, K. A.; Wang, R. Y. -R.; Arakawa, A. Science, Vol. 352, Issue 6293 https://doi.org/10.1126/science.aaf5023	journal	June 2016
Identification of a PP2A-interacting protein that functions as a negative regulator of phosphatase activity in the ATM/ATR signaling pathway McConnell, J. L.; Gomez, R. J.; McCorvey, L. R. A. Oncogene, Vol. 26, Issue 41 https://doi.org/10.1038/sj.onc.1210406	journal	March 2007
A sequential mechanism for clathrin cage disassembly by 70-kDa heat-shock cognate protein (Hsc70) and auxilin Rothnie, A.; Clarke, A. R.; Kuzmic, P. Proceedings of the National Academy of Sciences, Vol. 108, Issue 17 https://doi.org/10.1073/pnas.1018845108	journal	April 2011
The PP2A-Associated Protein 4 Is an Essential Inhibitor of Apoptosis Kong, M. Science, Vol. 306, Issue 5696 https://doi.org/10.1126/science.1100537	journal	October 2004
Interaction analysis of the heterotrimer formed by the phosphatase 2A catalytic subunit, α4 and the mammalian ortholog of yeast Tip41 (TIPRL): Identification of a novel PP2A heterotrimer Smetana, Juliana H. C.; Zanchin, Nilson I. T. FEBS Journal, Vol. 274, Issue 22 https://doi.org/10.1111/j.1742-4658.2007.06112.x	journal	October 2007
Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme Cho, Uhn Soo; Xu, Wenqing Nature, Vol. 445, Issue 7123 https://doi.org/10.1038/nature05351	journal	November 2006
Structure of a Protein Phosphatase 2A Holoenzyme: Insights into B55-Mediated Tau Dephosphorylation Xu, Yanhui; Chen, Yu; Zhang, Ping Molecular Cell, Vol. 31, Issue 6 https://doi.org/10.1016/j.molcel.2008.08.006	journal	September 2008
A positive role of mammalian Tip41-like protein, TIPRL, in the amino-acid dependent mTORC1-signaling pathway through interaction with PP2A Nakashima, Akio; Tanimura-Ito, Keiko; Oshiro, Noriko FEBS Letters, Vol. 587, Issue 18 https://doi.org/10.1016/j.febslet.2013.07.027	journal	July 2013
Brain protein phosphatase 2A: Developmental regulation and distinct cellular and subcellular localization by B subunits Strack, Stefan; Zaucha, Julie A.; Ebner, Ford F. The Journal of Comparative Neurology, Vol. 392, Issue 4 https://doi.org/10.1002/(SICI)1096-9861(19980323)392:4<515::AID-CNE8>3.0.CO;2-3	journal	March 1998
Structure of Protein Phosphatase 2A Core Enzyme Bound to Tumor-Inducing Toxins Xing, Yongna; Xu, Yanhui; Chen, Yu Cell, Vol. 127, Issue 2 https://doi.org/10.1016/j.cell.2006.09.025	journal	October 2006
Protein phosphatase 2A methylation: a link between elevated plasma homocysteine and Alzheimer's Disease Vafai, Scott B.; Stock, Jeffry B. FEBS Letters, Vol. 518, Issue 1-3 https://doi.org/10.1016/S0014-5793(02)02702-3	journal	April 2002
How good are my data and what is the resolution? Evans, Philip R.; Murshudov, Garib N. Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7 https://doi.org/10.1107/S0907444913000061	journal	June 2013
Structural basis of PP2A activation by PTPA, an ATP-dependent activation chaperone Guo, Feng; Stanevich, Vitali; Wlodarchak, Nathan Cell Research, Vol. 24, Issue 2 https://doi.org/10.1038/cr.2013.138	journal	October 2013
PP2A: the expected tumor suppressor Janssens, Veerle; Goris, Jozef; Van Hoof, Christine Current Opinion in Genetics & Development, Vol. 15, Issue 1 https://doi.org/10.1016/j.gde.2004.12.004	journal	February 2005
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
Involvement of PP2A in viral and cellular transformation Arroyo, Jason D.; Hahn, William C. Oncogene, Vol. 24, Issue 52 https://doi.org/10.1038/sj.onc.1209038	journal	November 2005
Chaperone machines for protein folding, unfolding and disaggregation Saibil, Helen Nature Reviews Molecular Cell Biology, Vol. 14, Issue 10 https://doi.org/10.1038/nrm3658	journal	September 2013
Crystal structure of the human Tip41 orthologue, TIPRL, reveals a novel fold and a binding site for the PP2Ac C-terminus Scorsato, Valéria; Lima, Tatiani B.; Righetto, Germanna L. Scientific Reports, Vol. 6, Issue 1 https://doi.org/10.1038/srep30813	journal	August 2016
Structure of the Ca2+-dependent PP2A heterotrimer and insights into Cdc6 dephosphorylation Wlodarchak, Nathan; Guo, Feng; Satyshur, Kenneth A. Cell Research, Vol. 23, Issue 7 https://doi.org/10.1038/cr.2013.77	journal	June 2013
Disassembly of Transcriptional Regulatory Complexes by Molecular Chaperones Freeman, B. C. Science, Vol. 296, Issue 5576 https://doi.org/10.1126/science.1073051	journal	June 2002
The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data: Figure 1. Cerami, Ethan; Gao, Jianjiong; Dogrusoz, Ugur Cancer Discovery, Vol. 2, Issue 5 https://doi.org/10.1158/2159-8290.CD-12-0095	journal	May 2012
Molecular chaperones in protein folding and proteostasis Hartl, F. Ulrich; Bracher, Andreas; Hayer-Hartl, Manajit Nature, Vol. 475, Issue 7356 https://doi.org/10.1038/nature10317	journal	July 2011
Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits Tolstykh, T. The EMBO Journal, Vol. 19, Issue 21 https://doi.org/10.1093/emboj/19.21.5682	journal	November 2000
Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling Janssens, Veerle; Goris, Jozef Biochemical Journal, Vol. 353, Issue 3 https://doi.org/10.1042/bj3530417	journal	January 2001
α4 Is an Essential Regulator of PP2A Phosphatase Activity Kong, Mei; Ditsworth, Dara; Lindsten, Tullia Molecular Cell, Vol. 36, Issue 1 https://doi.org/10.1016/j.molcel.2009.09.025	journal	October 2009
Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40 Chen, Yu; Xu, Yanhui; Bao, Qing Nature Structural & Molecular Biology, Vol. 14, Issue 6 https://doi.org/10.1038/nsmb1254	journal	May 2007
Structure of the Protein Phosphatase 2A Holoenzyme Xu, Yanhui; Xing, Yongna; Chen, Yu Cell, Vol. 127, Issue 6 https://doi.org/10.1016/j.cell.2006.11.033	journal	December 2006
Inhibition of MKK7–JNK by the TOR Signaling Pathway Regulator-Like Protein Contributes to Resistance of HCC Cells to TRAIL-Induced Apoptosis Song, In Sung; Jun, Soo Young; Na, Hee–Jun Gastroenterology, Vol. 143, Issue 5 https://doi.org/10.1053/j.gastro.2012.07.103	journal	November 2012
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
Structural Insights into the Tumor-Promoting Function of the MTDH-SND1 Complex Guo, Feng; Wan, Liling; Zheng, Aiping Cell Reports, Vol. 8, Issue 6 https://doi.org/10.1016/j.celrep.2014.08.033	journal	September 2014
Recurrent PPP2R1A Mutations in Uterine Cancer Act through a Dominant-Negative Mechanism to Promote Malignant Cell Growth Haesen, Dorien; Abbasi Asbagh, Layka; Derua, Rita Cancer Research, Vol. 76, Issue 19 https://doi.org/10.1158/0008-5472.CAN-15-3342	journal	August 2016
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Macromolecular TLS Refinement in REFMAC at Moderate Resolutions Winn, Martyn D.; Murshudov, Garib N.; Papiz, Miroslav Z. Methods in Enzymology https://doi.org/10.1016/S0076-6879(03)74014-2	book	January 2003
B cell receptor-associated protein 4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A Murata, K.; Wu, J.; Brautigan, D. L. Proceedings of the National Academy of Sciences, Vol. 94, Issue 20 https://doi.org/10.1073/pnas.94.20.10624	journal	September 1997
A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain. Lee, J.; Chen, Y.; Tolstykh, T. Proceedings of the National Academy of Sciences, Vol. 93, Issue 12 https://doi.org/10.1073/pnas.93.12.6043	journal	June 1996
Purification of Porcine Brain Protein Phosphatase 2A Leucine Carboxyl Methyltransferase and Cloning of the Human Homologue ^† ^, ^‡ De Baere, I.; Derua, R.; Janssens, V. Biochemistry, Vol. 38, Issue 50 https://doi.org/10.1021/bi991646a	journal	December 1999
Prevalence and architecture of de novo mutations in developmental disorders Nature, Vol. 542, Issue 7642, p. 433-438 https://doi.org/10.1038/nature21062	journal	January 2017
Downregulation of Protein Phosphatase 2A Carboxyl Methylation and Methyltransferase May Contribute to Alzheimer Disease Pathogenesis Sontag, Estelle; Hladik, Christa; Montgomery, Lisa Journal of Neuropathology & Experimental Neurology, Vol. 63, Issue 10 https://doi.org/10.1093/jnen/63.10.1080	journal	October 2004
De novo missense variants in PPP2R5D are associated with intellectual disability, macrocephaly, hypotonia, and autism Shang, Linshan; Henderson, Lindsay B.; Cho, Megan T. neurogenetics, Vol. 17, Issue 1 https://doi.org/10.1007/s10048-015-0466-9	journal	November 2015
The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability Niesen, Frank H.; Berglund, Helena; Vedadi, Masoud Nature Protocols, Vol. 2, Issue 9 https://doi.org/10.1038/nprot.2007.321	journal	September 2007
The Structural Basis for Tight Control of PP2A Methylation and Function by LCMT-1 Stanevich, Vitali; Jiang, Li; Satyshur, Kenneth A. Molecular Cell, Vol. 41, Issue 3 https://doi.org/10.1016/j.molcel.2010.12.030	journal	February 2011
Protein phosphatase 2A: a panoply of enzymes Virshup, David M. Current Opinion in Cell Biology, Vol. 12, Issue 2 https://doi.org/10.1016/S0955-0674(99)00074-5	journal	April 2000
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Regulation of Protein Phosphatase 2A Catalytic Activity by alpha4 Protein and Its Yeast Homolog Tap42 Nanahoshi, Masakazu; Nishiuma, Teruaki; Tsujishita, Yosuke Biochemical and Biophysical Research Communications, Vol. 251, Issue 2 https://doi.org/10.1006/bbrc.1998.9493	journal	October 1998
Matrix methods for solving protein substructures of chlorine and sulfur from anomalous data de Graaff, Rudolf A. G.; Hilge, Mark; van der Plas, Jaco L. Acta Crystallographica Section D Biological Crystallography, Vol. 57, Issue 12 https://doi.org/10.1107/S0907444901016535	journal	November 2001
TIPRL Inhibits Protein Phosphatase 4 Activity and Promotes H2AX Phosphorylation in the DNA Damage Response Rosales, Kimberly Romero; Reid, Michael A.; Yang, Ying PLOS ONE, Vol. 10, Issue 12 https://doi.org/10.1371/journal.pone.0145938	journal	December 2015
Mechanisms of the Scaffold Subunit in Facilitating Protein Phosphatase 2A Methylation Stanevich, Vitali; Zheng, Aiping; Guo, Feng PLoS ONE, Vol. 9, Issue 1 https://doi.org/10.1371/journal.pone.0086955	journal	January 2014

Similar Records

The Structural Basis for Tight Control of PP2A Methylation and Function by LCMT-1

Journal Article · Sat Dec 31 00:00:00 EST 2011 · Molecular Cell · OSTI ID:1418027

Stanevich, V; Jiang, L; Satyshur, K; +6 more

The Structural Basis for Tight Control of PP2A Methylation and Function by LCMT-1

Journal Article · Tue May 29 00:00:00 EDT 2012 · Mol. Cell · OSTI ID:1418027

Stanevich, Vitali; Jiang, Li; Satyshur, Kenneth A; +6 more

Structure of the Protein Phosphatase 2A Holoenzyme

Journal Article · Sun Jan 01 00:00:00 EST 2006 · Cell · OSTI ID:1418027

Xu, Y; Xing, Y; Chen, Y; +7 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES

Title: Methylation-regulated decommissioning of multimeric PP2A complexes

Citation Formats

References (56)

Similar Records

Related Subjects