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Structure and mechanism of the phosphotyrosyl phosphatase activator.

Chao Y, Xing Y, Chen Y, Xu Y, Lin Z, Li Z, Jeffrey PD, Stock JB, Shi Y
Mol Cell 23 535-46 (2006)
Cited: 31 times
EuropePMC logo PMID: 16916641

Abstract

Phosphotyrosyl phosphatase activator (PTPA), also known as PP2A phosphatase activator, is a conserved protein from yeast to human. Here we report the 1.9 A crystal structure of human PTPA, which reveals a previously unreported fold consisting of three subdomains: core, lid, and linker. Structural analysis uncovers a highly conserved surface patch, which borders the three subdomains, and an associated deep pocket located between the core and the linker subdomains. The conserved surface patch and the deep pocket are responsible for binding to PP2A and ATP, respectively. PTPA and PP2A A-C dimer together constitute a composite ATPase. PTPA binding to PP2A results in a dramatic alteration of substrate specificity, with enhanced phosphotyrosine phosphatase activity and decreased phosphoserine phosphatase activity. This function of PTPA strictly depends on the composite ATPase activity. These observations reveal significant insights into the function and mechanism of PTPA and have important ramifications for understanding PP2A function.

Articles - 2hv6 mentioned but not cited (1)

  1. Structural basis of PP2A activation by PTPA, an ATP-dependent activation chaperone. Guo F, Stanevich V, Wlodarchak N, Sengupta R, Jiang L, Satyshur KA, Xing Y. Cell Res 24 190-203 (2014)


Reviews citing this publication (7)

  1. Serine/threonine phosphatases: mechanism through structure. Shi Y. Cell 139 468-484 (2009)
  2. The biogenesis of active protein phosphatase 2A holoenzymes: a tightly regulated process creating phosphatase specificity. Sents W, Ivanova E, Lambrecht C, Haesen D, Janssens V. FEBS J 280 644-661 (2013)
  3. SV40 small T antigen and PP2A phosphatase in cell transformation. Sablina AA, Hahn WC. Cancer Metastasis Rev 27 137-146 (2008)
  4. Assembly and structure of protein phosphatase 2A. Shi Y. Sci China C Life Sci 52 135-146 (2009)
  5. Protein phosphatases of Saccharomyces cerevisiae. Offley SR, Schmidt MC. Curr Genet 65 41-55 (2019)
  6. Tau Protein Interaction Partners and Their Roles in Alzheimer's Disease and Other Tauopathies. Sinsky J, Pichlerova K, Hanes J. Int J Mol Sci 22 9207 (2021)
  7. Protein carboxyl methylation and the biochemistry of memory. Li Z, Stock JB. Biol Chem 390 1087-1096 (2009)

Articles citing this publication (23)

  1. An integrated workflow for charting the human interaction proteome: insights into the PP2A system. Glatter T, Wepf A, Aebersold R, Gstaiger M. Mol Syst Biol 5 237 (2009)
  2. Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Xing Y, Xu Y, Chen Y, Jeffrey PD, Chao Y, Lin Z, Li Z, Strack S, Stock JB, Shi Y. Cell 127 341-353 (2006)
  3. Structure of a protein phosphatase 2A holoenzyme: insights into B55-mediated Tau dephosphorylation. Xu Y, Chen Y, Zhang P, Jeffrey PD, Shi Y. Mol Cell 31 873-885 (2008)
  4. The structural basis for tight control of PP2A methylation and function by LCMT-1. Stanevich V, Jiang L, Satyshur KA, Li Y, Jeffrey PD, Li Z, Menden P, Semmelhack MF, Xing Y. Mol Cell 41 331-342 (2011)
  5. Generation of active protein phosphatase 2A is coupled to holoenzyme assembly. Hombauer H, Weismann D, Mudrak I, Stanzel C, Fellner T, Lackner DH, Ogris E. PLoS Biol 5 e155 (2007)
  6. Structural and biochemical insights into the regulation of protein phosphatase 2A by small t antigen of SV40. Chen Y, Xu Y, Bao Q, Xing Y, Li Z, Lin Z, Stock JB, Jeffrey PD, Shi Y. Nat Struct Mol Biol 14 527-534 (2007)
  7. RNA polymerase II termination involves C-terminal-domain tyrosine dephosphorylation by CPF subunit Glc7. Schreieck A, Easter AD, Etzold S, Wiederhold K, Lidschreiber M, Cramer P, Passmore LA. Nat Struct Mol Biol 21 175-179 (2014)
  8. Structure of the Ca2+-dependent PP2A heterotrimer and insights into Cdc6 dephosphorylation. Wlodarchak N, Guo F, Satyshur KA, Jiang L, Jeffrey PD, Sun T, Stanevich V, Mumby MC, Xing Y. Cell Res 23 931-946 (2013)
  9. Dephosphorylation of the core clock protein KaiC in the cyanobacterial KaiABC circadian oscillator proceeds via an ATP synthase mechanism. Egli M, Mori T, Pattanayek R, Xu Y, Qin X, Johnson CH. Biochemistry 51 1547-1558 (2012)
  10. Targeted disruption of the PME-1 gene causes loss of demethylated PP2A and perinatal lethality in mice. Ortega-Gutiérrez S, Leung D, Ficarro S, Peters EC, Cravatt BF. PLoS One 3 e2486 (2008)
  11. Role of Pin1 protein in the pathogenesis of nonalcoholic steatohepatitis in a rodent model. Nakatsu Y, Otani Y, Sakoda H, Zhang J, Guo Y, Okubo H, Kushiyama A, Fujishiro M, Kikuch T, Fukushima T, Ohno H, Tsuchiya Y, Kamata H, Nagamachi A, Inaba T, Nishimura F, Katagiri H, Takahashi S, Kurihara H, Uchida T, Asano T. J Biol Chem 287 44526-44535 (2012)
  12. PTPA activates protein phosphatase-2A through reducing its phosphorylation at tyrosine-307 with upregulation of protein tyrosine phosphatase 1B. Luo Y, Nie YJ, Shi HR, Ni ZF, Wang Q, Wang JZ, Liu GP. Biochim Biophys Acta 1833 1235-1243 (2013)
  13. Mechanisms of the scaffold subunit in facilitating protein phosphatase 2A methylation. Stanevich V, Zheng A, Guo F, Jiang L, Wlodarchak N, Xing Y. PLoS One 9 e86955 (2014)
  14. Arabidopsis PHOSPHOTYROSYL PHOSPHATASE ACTIVATOR is essential for PROTEIN PHOSPHATASE 2A holoenzyme assembly and plays important roles in hormone signaling, salt stress response, and plant development. Chen J, Hu R, Zhu Y, Shen G, Zhang H. Plant Physiol 166 1519-1534 (2014)
  15. Phosphotyrosyl phosphatase activator facilitates localization of Miranda through dephosphorylation in dividing neuroblasts. Zhang F, Huang ZX, Bao H, Cong F, Wang H, Chai PC, Xi Y, Ge W, Somers WG, Yang Y, Cai Y, Yang X. Development 143 35-44 (2016)
  16. PhosphoTyrosyl phosphatase activator of Plasmodium falciparum: identification of its residues involved in binding to and activation of PP2A. Vandomme A, Fréville A, Cailliau K, Cailliau K, Kalamou H, Bodart JF, Khalife J, Pierrot C. Int J Mol Sci 15 2431-2453 (2014)
  17. Crystal structure of the human Tip41 orthologue, TIPRL, reveals a novel fold and a binding site for the PP2Ac C-terminus. Scorsato V, Lima TB, Righetto GL, Zanchin NI, Brandão-Neto J, Sandy J, Pereira HD, Ferrari ÁJ, Gozzo FC, Smetana JH, Aparicio R. Sci Rep 6 30813 (2016)
  18. Proteomic Identification of Heat Shock-Induced Danger Signals in a Melanoma Cell Lysate Used in Dendritic Cell-Based Cancer Immunotherapy. González FE, Chernobrovkin A, Pereda C, García-Salum T, Tittarelli A, López MN, Salazar-Onfray F, Zubarev RA. J Immunol Res 2018 3982942 (2018)
  19. RNA polymerase II degradation in response to rapamycin is not mediated through ubiquitylation. Jouvet N, Poschmann J, Douville J, Marrakchi R, Ramotar D. Biochem Biophys Res Commun 413 248-253 (2011)
  20. A PP2A active site mutant impedes growth and causes misregulation of native catalytic subunit expression. Lizotte DL, Blakeslee JJ, Siryaporn A, Heath JT, DeLong A. J Cell Biochem 103 1309-1325 (2008)
  21. A variant at 9q34.11 is associated with HLA-DQB1*06:02 negative essential hypersomnia. Miyagawa T, Khor SS, Toyoda H, Kanbayashi T, Imanishi A, Sagawa Y, Kotorii N, Kotorii T, Ariyoshi Y, Hashizume Y, Ogi K, Hiejima H, Kamei Y, Hida A, Miyamoto M, Ikegami A, Wada Y, Takami M, Higashiyama Y, Miyake R, Kondo H, Fujimura Y, Tamura Y, Taniyama Y, Omata N, Tanaka Y, Moriya S, Furuya H, Kato M, Kawamura Y, Otowa T, Miyashita A, Kojima H, Saji H, Shimada M, Yamasaki M, Kobayashi T, Misawa R, Shigematsu Y, Kuwano R, Sasaki T, Ishigooka J, Wada Y, Tsuruta K, Chiba S, Tanaka F, Yamada N, Okawa M, Kuroda K, Kume K, Hirata K, Uchimura N, Shimizu T, Inoue Y, Honda Y, Mishima K, Honda M, Tokunaga K. J Hum Genet 63 1259-1267 (2018)
  22. PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability. Fevga C, Tesson C, Carreras Mascaro A, Courtin T, van Coller R, Sakka S, Ferraro F, Farhat N, Bardien S, Damak M, Carr J, Ferrien M, Boumeester V, Hundscheid J, Grillenzoni N, Kessissoglou IA, Kuipers DJS, Quadri M, French and Mediterranean Parkinson disease Genetics Study Group, International Parkinsonism Genetics Network, Corvol JC, Mhiri C, Hassan BA, Breedveld GJ, Lesage S, Mandemakers W, Brice A, Bonifati V. Brain 146 1496-1510 (2023)
  23. The PP2A/4/6 subfamily of phosphoprotein phosphatases regulates DAF-16 and confers resistance to environmental stress in postreproductive adult C. elegans. Rivard RS, Morris JM, Youngman MJ. PLoS One 15 e0229812 (2020)


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