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The third conformation of p38α MAP kinase observed in phosphorylated p38α and in solution.

Akella R, Min X, Wu Q, Gardner KH, Goldsmith EJ
Structure 18 1571-8 (2010)
Cited: 27 times
EuropePMC logo PMID: 21134636

Abstract

MAPKs engage substrates, MAP2Ks, and phosphatases via a docking groove in the C-terminal domain of the kinase. Prior crystallographic studies on the unphosphorylated MAPKs p38α and ERK2 defined the docking groove and revealed long-range conformational changes affecting the activation loop and active site of the kinase induced by peptide. Solution NMR data presented here for unphosphorylated p38α with a MEK3b-derived peptide (p38α/pepMEK3b) validate these findings. Crystallograhic data from doubly phosphorylated active p38α (p38α/T∗GY∗/pepMEK3b) reveal a structure similar to unphosphorylated p38α/MEK3b, and distinct from phosphorylated p38γ (p38γ/T∗GY∗) and ERK2 (ERK2/T∗EY∗). The structure supports the idea that MAP kinases adopt three distinct conformations: unphosphorylated, phosphorylated, and a docking peptide-induced form.

Reviews - 3p4k mentioned but not cited (1)

  1. Molecular basis of MAP kinase regulation. Peti W, Page R. Protein Sci 22 1698-1710 (2013)

Articles - 3p4k mentioned but not cited (3)

  1. p38α Mitogen-Activated Protein Kinase Is a Druggable Target in Pancreatic Adenocarcinoma. Yang L, Sun X, Ye Y, Lu Y, Zuo J, Liu W, Elcock A, Zhu S. Front Oncol 9 1294 (2019)
  2. Covalent flexible peptide docking in Rosetta. Tivon B, Gabizon R, Somsen BA, Cossar PJ, Ottmann C, London N. Chem Sci 12 10836-10847 (2021)
  3. A novel p38 MAPK docking-groove-targeted compound is a potent inhibitor of inflammatory hyperalgesia. Willemen HL, Campos PM, Lucas E, Morreale A, Gil-Redondo R, Agut J, González FV, Ramos P, Heijnen C, Mayor F, Kavelaars A, Murga C. Biochem J 459 427-439 (2014)


Reviews citing this publication (2)

  1. MAP kinase modules: the excursion model and the steps that count. Piala AT, Humphreys JM, Goldsmith EJ. Biophys J 107 2006-2015 (2014)
  2. Three-dimensional docking in the MAPK p38α. Goldsmith EJ. Sci Signal 4 pe47 (2011)

Articles citing this publication (21)

  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. Dynamic activation and regulation of the mitogen-activated protein kinase p38. Kumar GS, Clarkson MW, Kunze MBA, Granata D, Wand AJ, Lindorff-Larsen K, Page R, Peti W. Proc Natl Acad Sci U S A 115 4655-4660 (2018)
  3. Allosteric enhancement of MAP kinase p38α's activity and substrate selectivity by docking interactions. Tokunaga Y, Takeuchi K, Takahashi H, Shimada I. Nat Struct Mol Biol 21 704-711 (2014)
  4. Solution NMR insights into docking interactions involving inactive ERK2. Piserchio A, Warthaka M, Devkota AK, Kaoud TS, Lee S, Abramczyk O, Ren P, Dalby KN, Ghose R. Biochemistry 50 3660-3672 (2011)
  5. Structural Basis for the Subversion of MAP Kinase Signaling by an Intrinsically Disordered Parasite Secreted Agonist. Pellegrini E, Palencia A, Braun L, Kapp U, Bougdour A, Belrhali H, Bowler MW, Hakimi MA. Structure 25 16-26 (2017)
  6. Precisely ordered phosphorylation reactions in the p38 mitogen-activated protein (MAP) kinase cascade. Humphreys JM, Piala AT, Akella R, He H, Goldsmith EJ. J Biol Chem 288 23322-23330 (2013)
  7. X-ray structure of p38α bound to TAK-715: comparison with three classic inhibitors. Azevedo R, van Zeeland M, Raaijmakers H, Kazemier B, de Vlieg J, Oubrie A. Acta Crystallogr D Biol Crystallogr 68 1041-1050 (2012)
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  9. The differential regulation of p38α by the neuronal kinase interaction motif protein tyrosine phosphatases, a detailed molecular study. Francis DM, Kumar GS, Koveal D, Tortajada A, Page R, Peti W. Structure 21 1612-1623 (2013)
  10. Docking interactions of hematopoietic tyrosine phosphatase with MAP kinases ERK2 and p38α. Piserchio A, Francis DM, Koveal D, Dalby KN, Page R, Peti W, Ghose R. Biochemistry 51 8047-8049 (2012)
  11. Functional divergence caused by mutations in an energetic hotspot in ERK2. Taylor CA, Cormier KW, Keenan SE, Earnest S, Stippec S, Wichaidit C, Juang YC, Wang J, Shvartsman SY, Goldsmith EJ, Cobb MH. Proc Natl Acad Sci U S A 116 15514-15523 (2019)
  12. A Phosphorylated Intermediate in the Activation of WNK Kinases. Akella R, Drozdz MA, Humphreys JM, Jiou J, Durbacz MZ, Mohammed ZJ, He H, Liwocha J, Sekulski K, Goldsmith EJ. Biochemistry 59 1747-1755 (2020)
  13. Membrane skeletal association and post-translational allosteric regulation of Toxoplasma gondii GAPDH1. Dubey R, Staker BL, Foe IT, Bogyo M, Myler PJ, Ngô HM, Gubbels MJ. Mol Microbiol 103 618-634 (2017)
  14. NMR spectroscopic investigations of the activated p38α mitogen-activated protein kinase. Nielsen G, Schwalbe H. Chembiochem 12 2599-2607 (2011)
  15. Structural basis for the regulation of the mitogen-activated protein (MAP) kinase p38α by the dual specificity phosphatase 16 MAP kinase binding domain in solution. Kumar GS, Zettl H, Page R, Peti W. J Biol Chem 288 28347-28356 (2013)
  16. A Dynamic Switch in Inactive p38γ Leads to an Excited State on the Pathway to an Active Kinase. Aoto PC, Stanfield RL, Wilson IA, Dyson HJ, Wright PE. Biochemistry 58 5160-5172 (2019)
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  18. Kinetic and mechanistic studies of p38α MAP kinase phosphorylation by MKK6. Wang YL, Zhang YY, Lu C, Zhang W, Deng H, Wu JW, Wang J, Wang ZX. FEBS J 286 1030-1052 (2019)
  19. The interaction of p38 with its upstream kinase MKK6. Kumar GS, Page R, Peti W. Protein Sci 30 908-913 (2021)
  20. Linear motif specificity in signaling through p38α and ERK2 mitogen-activated protein kinases. Torres Robles J, Lou HJ, Shi G, Pan PL, Turk BE. Proc Natl Acad Sci U S A 120 e2316599120 (2023)
  21. Structural basis of a redox-dependent conformational switch that regulates the stress kinase p38α. Pous J, Baginski B, Martin-Malpartida P, González L, Scarpa M, Aragon E, Ruiz L, Mees RA, Iglesias-Fernández J, Orozco M, Nebreda AR, Macias MJ. Nat Commun 14 7920 (2023)


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