Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board: Buchner, Johannes / Lei, Ming / Ludwig, Stephan / Sies, Helmut / Thomas, Douglas D. / Turk, Boris / Wittinghofer, Alfred


IMPACT FACTOR 2017: 3.022

CiteScore 2017: 2.81

SCImago Journal Rank (SJR) 2017: 1.562
Source Normalized Impact per Paper (SNIP) 2017: 0.705

Online
ISSN
1437-4315
See all formats and pricing
More options …
Volume 395, Issue 7-8

Issues

Structural basis for PTPA interaction with the invariant C-terminal tail of PP2A

Christian Löw
  • Corresponding author
  • Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Scheeles väg 2, S-17177 Stockholm, Sweden
  • European Molecular Biology Laboratory, Hamburg Outstation c/o DESY, Notkestrasse 85, 22603 Hamburg, Germany
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Esben M. Quistgaard
  • Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Scheeles väg 2, S-17177 Stockholm, Sweden
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Michael Kovermann
  • Fachgruppe Biophysik, Institut für Physik, Martin-Luther-Universität Halle-Wittenberg, Betty-Heimann-Strasse 7, D-06120 Halle/Saale, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Madhanagopal Anandapadamanaban
  • Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Scheeles väg 2, S-17177 Stockholm, Sweden
  • Department of Physics, Chemistry and Biology, Linköping University, S-58183 Linköping, Sweden
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Jochen Balbach
  • Fachgruppe Biophysik, Institut für Physik, Martin-Luther-Universität Halle-Wittenberg, Betty-Heimann-Strasse 7, D-06120 Halle/Saale, Germany
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Pär Nordlund
  • Corresponding author
  • Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Scheeles väg 2, S-17177 Stockholm, Sweden
  • School of Biological Sciences, Nanyang Technological University, 639798 Singapore, Singapore
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2014-07-08 | DOI: https://doi.org/10.1515/hsz-2014-0106

Abstract

Protein phosphatase 2A (PP2A) is a highly abundant heterotrimeric Ser/Thr phosphatase involved in the regulation of a variety of signaling pathways. The PP2A phosphatase activator (PTPA) is an ATP-dependent activation chaperone, which plays a key role in the biogenesis of active PP2A. The C-terminal tail of the catalytic subunit of PP2A is highly conserved and can undergo a number of posttranslational modifications that serve to regulate the function of PP2A. Here we have studied structurally the interaction of PTPA with the conserved C-terminal tail of the catalytic subunit carrying different posttranslational modifications. We have identified an additional interaction site for the invariant C-terminal tail of the catalytic subunit on PTPA, which can be modulated via posttranslational modifications. We show that phosphorylation of Tyr307PP2A-C or carboxymethylation of Leu309PP2A-C abrogates or diminishes binding of the C-terminal tail, whereas phosphorylation of Thr304PP2A-C is of no consequence. We suggest that the invariant C-terminal residues of the catalytic subunit can act as affinity enhancer for different PP2A interaction partners, including PTPA, and a different ‘code’ of posttranslational modifications can favour interactions to one subunit over others.

This article offers supplementary material which is provided at the end of the article.

Keywords: activation chaperone; phosphatase; posttranslational modification; signaling; X-ray structure

References

  • Cayla, X., Van Hoof, C., Bosch, M., Waelkens, E., Vandekerckhove, J., Peeters, B., Merlevede, W., and Goris, J. (1994). Molecular cloning, expression, and characterization of PTPA, a protein that activates the tyrosyl phosphatase activity of protein phosphatase 2A. J. Biol. Chem. 269, 15668–15675.Google Scholar

  • Chao, Y., Xing, Y., Chen, Y., Xu, Y., Lin, Z., Li, Z., Jeffrey, P.D., Stock, J.B., and Shi, Y. (2006). Structure and mechanism of the phosphotyrosyl phosphatase activator. Mol. Cell 23, 535–546.PubMedCrossrefGoogle Scholar

  • Chen, J., Martin, B.L., and Brautigan, D.L. (1992). Regulation of protein serine-threonine phosphatase type-2A by tyrosine phosphorylation. Science 257, 1261–1264.Google Scholar

  • Chen, Y., Xu, Y., Bao, Q., Xing, Y., Li, Z., Lin, Z., Stock, J.B., Jeffrey, P.D., and Shi, Y. (2007). Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40. Nat. Struct. Mol. Biol. 14, 527–534.CrossrefGoogle Scholar

  • Chen, V.B., Arendall, W.B., 3rd, Headd, J.J., Keedy, D.A., Immormino, R.M., Kapral, G.J., Murray, L.W., Richardson, J.S., and Richardson, D.C. (2010). MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr. D 66, 12–21.CrossrefGoogle Scholar

  • Cho, U.S. and Xu, W. (2007). Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 445, 53–57.Google Scholar

  • Cho, U.S., Morrone, S., Sablina, A.A., Arroyo, J.D., Hahn, W.C., and Xu, W. (2007). Structural basis of PP2A inhibition by small t antigen. PLoS Biol. 5, e202.CrossrefGoogle Scholar

  • De Baere, I., Derua, R., Janssens, V., Van Hoof, C., Waelkens, E., Merlevede, W., and Goris, J. (1999). Purification of porcine brain protein phosphatase 2A leucine carboxyl methyltransferase and cloning of the human homologue. Biochemistry 38, 16539–16547.Google Scholar

  • Delaglio, F., Grzesiek, S., Vuister, G.W., Zhu, G., Pfeifer, J., and Bax, A. (1995). NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J Biomol. NMR 6, 277–293.PubMedGoogle Scholar

  • DeLano, W. (2003). The PyMOL Molecular Graphics System. DeLano Scientific LLC. http://www.pymol.org.

  • Emsley, P., Lohkamp, B., Scott, W.G., and Cowtan, K. (2010). Features and development of Coot. Acta Crystallogr. D 66, 486–501.CrossrefGoogle Scholar

  • Fellner, T., Lackner, D.H., Hombauer, H., Piribauer, P., Mudrak, I., Zaragoza, K., Juno, C., and Ogris, E. (2003). A novel and essential mechanism determining specificity and activity of protein phosphatase 2A (PP2A) in vivo. Genes Dev. 17, 2138–2150.CrossrefPubMedGoogle Scholar

  • Gallego, M. and Virshup, D.M. (2005). Protein serine/threonine phosphatases: life, death, and sleeping. Curr. Opin. Cell Biol. 17, 197–202.CrossrefPubMedGoogle Scholar

  • Graslund, S., Sagemark, J., Berglund, H., Dahlgren, L.G., Flores, A., Hammarstrom, M., Johansson, I., Kotenyova, T., Nilsson, M., Nordlund, P., et al. (2008). The use of systematic N- and C-terminal deletions to promote production and structural studies of recombinant proteins. Protein Expr. Purif. 58, 210–221.CrossrefGoogle Scholar

  • Groves, M.R., Hanlon, N., Turowski, P., Hemmings, B.A., and Barford, D. (1999). The structure of the protein phosphatase 2A PR65/A subunit reveals the conformation of its 15 tandemly repeated HEAT motifs. Cell 96, 99–110.Google Scholar

  • Grzesiek, S., Stahl, S.J., Wingfield, P.T., and Bax, A. (1996). The CD4 determinant for downregulation by HIV-1 Nef directly binds to Nef. Mapping of the Nef binding surface by NMR. Biochemistry 35, 10256–10261.Google Scholar

  • Guo, F., Stanevich, V., Wlodarchak, N., Sengupta, R., Jiang, L., Satyshur, K.A., and Xing, Y. (2014). Structural basis of PP2A activation by PTPA, an ATP-dependent activation chaperone. Cell Res. 24, 190–203.CrossrefGoogle Scholar

  • Heijman, J., Dewenter, M., El-Armouche, A., and Dobrev, D. (2013). Function and regulation of serine/threonine phosphatases in the healthy and diseased heart. J. Mol. Cell Cardiol. 64, 90–98.Google Scholar

  • Huhn, J., Jeffrey, P.D., Larsen, K., Rundberget, T., Rise, F., Cox, N.R., Arcus, V., Shi, Y., and Miles, C.O. (2009). A structural basis for the reduced toxicity of dinophysistoxin-2. Chem. Res. Toxicol. 22, 1782–1786.PubMedGoogle Scholar

  • Hunter, T. (1995). Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell 80, 225–236.Google Scholar

  • Ikehara, T., Ikehara, S., Imamura, S., Shinjo, F., and Yasumoto, T. (2007). Methylation of the C-terminal leucine residue of the PP2A catalytic subunit is unnecessary for the catalytic activity and the binding of regulatory subunit (PR55/B). Biochem. Biophys. Res. Commun. 354, 1052–1057.Google Scholar

  • Janssens, V. and Goris, J. (2001). Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem. J. 353, 417–439.Google Scholar

  • Janssens, V., Longin, S., and Goris, J. (2008). PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail). Trends Biochem. Sci. 33, 113–121.Google Scholar

  • Jiang, L., Stanevich, V., Satyshur, K.A., Kong, M., Watkins, G.R., Wadzinski, B.E., Sengupta, R., and Xing, Y. (2013). Structural basis of protein phosphatase 2A stable latency. Nat. Commun. 4, 1699.CrossrefPubMedGoogle Scholar

  • Johnson, B.A. and Blevins, R.A. (1994). NMR View: a computer program for the visualization and analysis of NMR data. J. Biomol. NMR 4, 603–614.CrossrefGoogle Scholar

  • Kabsch, W. (2010). XDS. Acta Crystallogr. D 66, 125–132.Google Scholar

  • Lambrecht, C., Haesen, D., Sents, W., Ivanova, E., and Janssens, V. (2013). Structure, regulation, and pharmacological modulation of PP2A phosphatases. Methods Mol. Biol. 1053, 283–305.Google Scholar

  • Leulliot, N., Vicentini, G., Jordens, J., Quevillon-Cheruel, S., Schiltz, M., Barford, D., van Tilbeurgh, H., and Goris, J. (2006). Crystal structure of the PP2A phosphatase activator: implications for its PP2A-specific PPIase activity. Mol. Cell 23, 413–424.CrossrefGoogle Scholar

  • Löw, C., Jegerschold, C., Kovermann, M., Moberg, P., and Nordlund, P. (2012). Optimisation of over-expression in E. coli and biophysical characterisation of human membrane protein synaptogyrin 1. PLoS One 7, e38244.Google Scholar

  • Magnusdottir, A., Stenmark, P., Flodin, S., Nyman, T., Kotenyova, T., Graslund, S., Ogg, D., and Nordlund, P. (2009). The structure of the PP2A regulatory subunit B56γ: the remaining piece of the PP2A jigsaw puzzle. Proteins 74, 212–221.Google Scholar

  • McCoy, A.J., Grosse-Kunstleve, R.W., Adams, P.D., Winn, M.D., Storoni, L.C., and Read, R.J. (2007). Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674.CrossrefGoogle Scholar

  • Mumby, M.C. and Walter, G. (1993). Protein serine/threonine phosphatases: structure, regulation, and functions in cell growth. Physiol. Rev. 73, 673–699.Google Scholar

  • Ogris, E., Du, X., Nelson, K.C., Mak, E.K., Yu, X.X., Lane, W.S., and Pallas, D.C. (1999). A protein phosphatase methylesterase (PME-1) is one of several novel proteins stably associating with two inactive mutants of protein phosphatase 2A. J. Biol. Chem. 274, 14382–14391.Google Scholar

  • Quistgaard, E.M., Nordlund, P., and Löw, C. (2012). High-resolution insights into binding of unfolded polypeptides by the PPIase chaperone SlpA. FASEB J. 26, 4003–4013.PubMedCrossrefGoogle Scholar

  • Rempola, B., Kaniak, A., Migdalski, A., Rytka, J., Slonimski, P.P., and di Rago, J.P. (2000). Functional analysis of RRD1 (YIL153w) and RRD2 (YPL152w), which encode two putative activators of the phosphotyrosyl phosphatase activity of PP2A in Saccharomyces cerevisiae. Mol. Gen. Genet. 262, 1081–1092.Google Scholar

  • Sablina, A.A., Hector, M., Colpaert, N., and Hahn, W.C. (2010). Identification of PP2A complexes and pathways involved in cell transformation. Cancer Res. 70, 10474–10484.CrossrefGoogle Scholar

  • Schmitz, M.H., Held, M., Janssens, V., Hutchins, J.R., Hudecz, O., Ivanova, E., Goris, J., Trinkle-Mulcahy, L., Lamond, A.I., Poser, I., et al. (2010). Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-β1 as key mitotic exit regulators in human cells. Nat. Cell Biol. 12, 886–893.Google Scholar

  • Sents, W., Ivanova, E., Lambrecht, C., Haesen, D., and Janssens, V. (2013). The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity. FEBS J. 280, 644–661.Google Scholar

  • Shi, Y. (2009a). Assembly and structure of protein phosphatase 2A. Sci. China C Life Sci. 52, 135–146.CrossrefGoogle Scholar

  • Shi, Y. (2009b). Serine/threonine phosphatases: mechanism through structure. Cell 139, 468–484.Google Scholar

  • Stanevich, V., Jiang, L., Satyshur, K.A., Li, Y., Jeffrey, P.D., Li, Z., Menden, P., Semmelhack, M.F., and Xing, Y. (2011). The structural basis for tight control of PP2A methylation and function by LCMT-1. Mol. Cell 41, 331–342.Google Scholar

  • Tsai, M.L., Cronin, N., and Djordjevic, S. (2011). The structure of human leucine carboxyl methyltransferase 1 that regulates protein phosphatase PP2A. Acta Crystallogr. D 67, 14–24.CrossrefGoogle Scholar

  • Virshup, D.M. and Shenolikar, S. (2009). From promiscuity to precision: protein phosphatases get a makeover. Mol. Cell 33, 537–545.Google Scholar

  • Weigelt, J. (1998). Single scan, sensitivity- and gradient-enhanced TROSY for multidimensional NMR experiments (vol 120, pg 10778, 1998). J. Am. Chem. Soc. 120, 12706–12706.Google Scholar

  • Wlodarchak, N., Guo, F., Satyshur, K.A., Jiang, L., Jeffrey, P.D., Sun, T., Stanevich, V., Mumby, M.C., and Xing, Y. (2013). Structure of the Ca2+-dependent PP2A heterotrimer and insights into Cdc6 dephosphorylation. Cell Res. 23, 931–946.Google Scholar

  • Woestenenk, E.A., Hammarstrom, M., van den Berg, S., Hard, T., and Berglund, H. (2004). His tag effect on solubility of human proteins produced in Escherichia coli: a comparison between four expression vectors. J. Struct. Funct. Genomics 5, 217–229.CrossrefGoogle Scholar

  • Wurzenberger, C. and Gerlich, D.W. (2011). Phosphatases: providing safe passage through mitotic exit. Nat. Rev. Mol. Cell Biol. 12, 469–482.PubMedCrossrefGoogle Scholar

  • Xing, Y., Xu, Y., Chen, Y., Jeffrey, P.D., Chao, Y., Lin, Z., Li, Z., Strack, S., Stock, J.B., and Shi, Y. (2006). Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Cell 127, 341–353.Google Scholar

  • Xing, Y., Li, Z., Chen, Y., Stock, J.B., Jeffrey, P.D., and Shi, Y. (2008). Structural mechanism of demethylation and inactivation of protein phosphatase 2A. Cell 133, 154–163.Google Scholar

  • Xu, Y., Xing, Y., Chen, Y., Chao, Y., Lin, Z., Fan, E., Yu, J.W., Strack, S., Jeffrey, P.D., and Shi, Y. (2006). Structure of the protein phosphatase 2A holoenzyme. Cell 127, 1239–1251.Google Scholar

  • Xu, Y., Chen, Y., Zhang, P., Jeffrey, P.D., and Shi, Y. (2008). Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation. Mol. Cell 31, 873–885.CrossrefPubMedGoogle Scholar

About the article

Corresponding authors: Christian Löw, Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Scheeles väg 2, S-17177 Stockholm, Sweden; and European Molecular Biology Laboratory, Hamburg Outstation c/o DESY, Notkestrasse 85, 22603 Hamburg, Germany; and Pär Nordlund, Karolinska Institutet, Department of Medical Biochemistry and Biophysics, Scheeles väg 2, S-17177 Stockholm, Sweden; and School of Biological Sciences, Nanyang Technological University, 639798 Singapore, Singapore, e-mail: ,


Received: 2014-01-20

Accepted: 2014-05-20

Published Online: 2014-07-08

Published in Print: 2014-07-01


Citation Information: Biological Chemistry, Volume 395, Issue 7-8, Pages 881–889, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: https://doi.org/10.1515/hsz-2014-0106.

Export Citation

©2014 by Walter de Gruyter Berlin/Boston.Get Permission

Supplementary Article Materials

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Sara Reynhout, Sandra Jansen, Dorien Haesen, Siska van Belle, Sonja A. de Munnik, Ernie M.H.F. Bongers, Jolanda H. Schieving, Carlo Marcelis, Jeanne Amiel, Marlène Rio, Heather Mclaughlin, Roger Ladda, Susan Sell, Marjolein Kriek, Cacha M.P.C.D. Peeters-Scholte, Paulien A. Terhal, Koen L. van Gassen, Nienke Verbeek, Sonja Henry, Jessica Scott Schwoerer, Saleem Malik, Nicole Revencu, Carlos R. Ferreira, Ellen Macnamara, Hilde M.H. Braakman, Elise Brimble, Maura R.Z. Ruznikov, Matias Wagner, Philip Harrer, Dagmar Wieczorek, Alma Kuechler, Barak Tziperman, Ortal Barel, Bert B.A. de Vries, Christopher T. Gordon, Veerle Janssens, and Lisenka E.L.M. Vissers
The American Journal of Human Genetics, 2018
[2]
Otto Kauko and Jukka Westermarck
The International Journal of Biochemistry & Cell Biology, 2018
[3]
Valéria Scorsato, Tatiani B. Lima, Germanna L. Righetto, Nilson I. T. Zanchin, José Brandão-Neto, James Sandy, Humberto D’Muniz Pereira, Állan J. R. Ferrari, Fabio C. Gozzo, Juliana H. C. Smetana, and Ricardo Aparicio
Scientific Reports, 2016, Volume 6, Number 1
[4]
Nathan Wlodarchak and Yongna Xing
Critical Reviews in Biochemistry and Molecular Biology, 2016, Volume 51, Number 3, Page 162

Comments (0)

Please log in or register to comment.
Log in