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Structural basis of substrate recognition by hematopoietic tyrosine phosphatase.

Critton DA, Tortajada A, Stetson G, Peti W, Page R
Biochemistry 47 13336-45 (2008)
Related entries: 2hvl, 3d42, 3d44

Cited: 24 times
EuropePMC logo PMID: 19053285

Abstract

Hematopoietic tyrosine phosphatase (HePTP) is one of three members of the kinase interaction motif (KIM) phosphatase family which also includes STEP and PCPTP1. The KIM-PTPs are characterized by a 15 residue sequence, the KIM, which confers specific high-affinity binding to their only known substrates, the MAP kinases Erk and p38, an interaction which is critical for their ability to regulate processes such as T cell differentiation (HePTP) and neuronal signaling (STEP). The KIM-PTPs are also characterized by a unique set of residues in their PTP substrate binding loops, where 4 of the 13 residues are differentially conserved among the KIM-PTPs as compared to more than 30 other class I PTPs. One of these residues, T106 in HePTP, is either an aspartate or asparagine in nearly every other PTP. Using multiple techniques, we investigate the role of these KIM-PTP specific residues in order to elucidate the molecular basis of substrate recognition by HePTP. First, we used NMR spectroscopy to show that Erk2-derived peptides interact specifically with HePTP at the active site. Next, to reveal the molecular details of this interaction, we solved the high-resolution three-dimensional structures of two distinct HePTP-Erk2 peptide complexes. Strikingly, we were only able to obtain crystals of these transient complexes using a KIM-PTP specific substrate-trapping mutant, in which the KIM-PTP specific residue T106 was mutated to an aspartic acid (T106D). The introduced aspartate side chain facilitates the coordination of the bound peptides, thereby stabilizing the active dephosphorylation complex. These structures establish the essential role of HePTP T106 in restricting HePTP specificity to only those substrates which are able to interact with KIM-PTPs via the KIM (e.g., Erk2, p38). Finally, we describe how this interaction of the KIM is sufficient for overcoming the otherwise weak interaction at the active site of KIM-PTPs.

Articles - 2qdc mentioned but not cited (1)

  1. Visualizing active-site dynamics in single crystals of HePTP: opening of the WPD loop involves coordinated movement of the E loop. Critton DA, Tautz L, Page R. J Mol Biol 405 619-629 (2011)


Reviews citing this publication (5)

  1. Molecular basis of MAP kinase regulation. Peti W, Page R. Protein Sci 22 1698-1710 (2013)
  2. Strategies to optimize protein expression in E. coli. Francis DM, Page R. Curr Protoc Protein Sci Chapter 5 5.24.1-5.24.29 (2010)
  3. Revisiting protein kinase-substrate interactions: Toward therapeutic development. de Oliveira PS, Ferraz FA, Pena DA, Pramio DT, Morais FA, Schechtman D. Sci Signal 9 re3 (2016)
  4. Cellular biochemistry methods for investigating protein tyrosine phosphatases. Stanford SM, Ahmed V, Barrios AM, Bottini N. Antioxid Redox Signal 20 2160-2178 (2014)
  5. X-ray crystallography and NMR as tools for the study of protein tyrosine phosphatases. Gulerez IE, Gehring K. Methods 65 175-183 (2014)

Articles citing this publication (18)

  1. Structural basis of p38α regulation by hematopoietic tyrosine phosphatase. Francis DM, Różycki B, Koveal D, Hummer G, Page R, Peti W. Nat Chem Biol 7 916-924 (2011)
  2. Hypofunctional TrkA Accounts for the Absence of Pain Sensitization in the African Naked Mole-Rat. Omerbašić D, Smith ES, Moroni M, Homfeld J, Eigenbrod O, Bennett NC, Reznick J, Faulkes CG, Selbach M, Lewin GR. Cell Rep 17 748-758 (2016)
  3. Molecular mechanism of ERK dephosphorylation by striatal-enriched protein tyrosine phosphatase. Li R, Xie DD, Dong JH, Li H, Li KS, Su J, Chen LZ, Xu YF, Wang HM, Gong Z, Cui GY, Yu X, Wang K, Yao W, Xin T, Li MY, Xiao KH, An XF, Huo Y, Xu ZG, Sun JP, Pang Q. J Neurochem 128 315-329 (2014)
  4. Diverse levels of sequence selectivity and catalytic efficiency of protein-tyrosine phosphatases. Selner NG, Luechapanichkul R, Chen X, Neel BG, Zhang ZY, Knapp S, Bell CE, Pei D. Biochemistry 53 397-412 (2014)
  5. Resting and active states of the ERK2:HePTP complex. Francis DM, Różycki B, Tortajada A, Hummer G, Peti W, Page R. J Am Chem Soc 133 17138-17141 (2011)
  6. Inhibition of hematopoietic protein tyrosine phosphatase augments and prolongs ERK1/2 and p38 activation. Sergienko E, Xu J, Liu WH, Dahl R, Critton DA, Su Y, Brown BT, Chan X, Yang L, Bobkova EV, Vasile S, Yuan H, Rascon J, Colayco S, Sidique S, Cosford ND, Chung TD, Mustelin T, Page R, Lombroso PJ, Tautz L. ACS Chem Biol 7 367-377 (2012)
  7. Reciprocal allosteric regulation of p38γ and PTPN3 involves a PDZ domain-modulated complex formation. Chen KE, Lin SY, Wu MJ, Ho MR, Santhanam A, Chou CC, Meng TC, Wang AH. Sci Signal 7 ra98 (2014)
  8. Endogenous, regulatory cysteine sulfenylation of ERK kinases in response to proliferative signals. Keyes JD, Parsonage D, Yammani RD, Rogers LC, Kesty C, Furdui CM, Nelson KJ, Poole LB. Free Radic Biol Med 112 534-543 (2017)
  9. Substrate specificity and plasticity of FERM-containing protein tyrosine phosphatases. Chen KE, Li MY, Chou CC, Ho MR, Chen GC, Meng TC, Wang AH. Structure 23 653-664 (2015)
  10. Role of protein tyrosine phosphatase non-receptor type 7 in the regulation of TNF-α production in RAW 264.7 macrophages. Seo H, Lee IS, Park JE, Park SG, Lee DH, Park BC, Cho S. PLoS One 8 e78776 (2013)
  11. Specific dephosphorylation of Janus Kinase 2 by protein tyrosine phosphatases. Li J, Liu X, Chu H, Fu X, Li T, Hu L, Xing S, Li G, Gu J, Zhao ZJ. Proteomics 15 68-76 (2015)
  12. Inhibition of the Hematopoietic Protein Tyrosine Phosphatase by Phenoxyacetic Acids. Bobkova EV, Liu WH, Colayco S, Rascon J, Vasile S, Gasior C, Critton DA, Chan X, Dahl R, Su Y, Sergienko E, Chung TD, Mustelin T, Page R, Tautz L. ACS Med Chem Lett 2 113-118 (2011)
  13. Both Intrinsic Substrate Preference and Network Context Contribute to Substrate Selection of Classical Tyrosine Phosphatases. Palma A, Tinti M, Paoluzi S, Santonico E, Brandt BW, Brandt BW, Hooft van Huijsduijnen R, Masch A, Heringa J, Schutkowski M, Castagnoli L, Cesareni G. J Biol Chem 292 4942-4952 (2017)
  14. Effective cleavage of phosphodiester promoted by the zinc(II) and copper(II) inclusion complexes of β-cyclodextrin. Zhou YH, Chen LQ, Tao J, Shen JL, Gong DY, Yun RR, Cheng Y. J Inorg Biochem 163 176-184 (2016)
  15. SHP family protein tyrosine phosphatases adopt canonical active-site conformations in the apo and phosphate-bound states. Alicea-Velazquez NL, Boggon TJ. Protein Pept Lett 20 1039-1048 (2013)
  16. The interaction of p38 with its upstream kinase MKK6. Kumar GS, Page R, Peti W. Protein Sci 30 908-913 (2021)
  17. A New Paradigm for KIM-PTP Drug Discovery: Identification of Allosteric Sites with Potential for Selective Inhibition Using Virtual Screening and LEI Analysis. Adams J, Thornton BP, Tabernero L. Int J Mol Sci 22 12206 (2021)
  18. Structural insights into the pSer/pThr dependent regulation of the SHP2 tyrosine phosphatase in insulin and CD28 signaling. Zeke A, Takács T, Sok P, Németh K, Kirsch K, Egri P, Póti ÁL, Bento I, Tusnády GE, Reményi A. Nat Commun 13 5439 (2022)


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