Atomic structure of the MAP kinase ERK2 at 2.3 Å resolution

The structure of the MAP kinase ERK2, a ubiquitous protein kinase target for regulation by Ras and Raf, has been solved in its unphosphorylated low-activity conformation to a resolution of 2.3 A. The two domains of unphosphorylated ERK2 are farther apart than in the active conformation of cAMP-dependent protein kinase and the peptide-binding site is blocked by tyrosine 185, one of the two residues that are phosphorylated in the active enzyme. Activation of ERK2 is thus likely to involve both global and local conformational changes.

[1]  E. Krebs,et al.  ERK1 and ERK2, two microtubule-associated protein 2 kinases, mediate the phosphorylation of tyrosine hydroxylase at serine-31 in situ. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[2]  S. Hanks.  Eukaryotic protein kinases , 1991 .

[3]  T. A. Jones,et al.  A graphics model building and refinement system for macromolecules , 1978 .

[4]  Hong Sun,et al.  MKP-1 (3CH134), an immediate early gene product, is a dual specificity phosphatase that dephosphorylates MAP kinase in vivo , 1993, Cell.

[5]  M. Cobb,et al.  Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies. , 1991, Cell regulation.

[6]  M. Cobb,et al.  Regulation and properties of extracellular signal-regulated protein kinases 1 and 2 in vitro. , 1993, The Journal of biological chemistry.

[7]  N. Xuong,et al.  Software for a diffractometer with multiwire area detector. , 1985, Methods in enzymology.

[8]  M. Meyerson,et al.  Isolation of the human cdk2 gene that encodes the cyclin A- and adenovirus E1A-associated p33 kinase , 1991, Nature.

[9]  N. Xuong,et al.  Structure of the mammalian catalytic subunit of cAMP-dependent protein kinase and an inhibitor peptide displays an open conformation. , 1993, Acta crystallographica. Section D, Biological crystallography.

[10]  C. Slaughter,et al.  An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. , 1990, Science.

[11]  G A Petsko,et al.  Mapping protein dynamics by X-ray diffraction. , 1985, Progress in biophysics and molecular biology.

[12]  J. Zou,et al.  Improved methods for building protein models in electron density maps and the location of errors in these models. , 1991, Acta crystallographica. Section A, Foundations of crystallography.

[13]  C. Marshall,et al.  A dominant-negative mutant of raf blocks mitogen-activated protein kinase activation by growth factors and oncogenic p21ras. , 1993, The Journal of biological chemistry.

[14]  D E Koshland,et al.  Structure of a bacterial enzyme regulated by phosphorylation, isocitrate dehydrogenase. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[15]  G. Drewes,et al.  Mitogen activated protein (MAP) kinase transforms tau protein into an Alzheimer‐like state. , 1992, The EMBO journal.

[16]  E. Goldsmith,et al.  Crystallization and preliminary X-ray studies of extracellular signal-regulated kinase-2/MAP kinase with an incorporated His-tag. , 1993, Journal of molecular biology.

[17]  M. Perutz.  Stereochemistry of Cooperative Effects in Haemoglobin: Haem–Haem Interaction and the Problem of Allostery , 1970, Nature.

[18]  K. Guan,et al.  Dephosphorylation and inactivation of the mitogen-activated protein kinase by a mitogen-induced Thr/Tyr protein phosphatase. , 1993, The Journal of biological chemistry.

[19]  C. Lange-Carter,et al.  A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf , 1993, Science.

[20]  S. Pelech,et al.  Definition of a consensus sequence for peptide substrate recognition by p44mpk, the meiosis-activated myelin basic protein kinase. , 1991, The Journal of biological chemistry.

[21]  R. Davis,et al.  Identification of substrate recognition determinants for human ERK1 and ERK2 protein kinases. , 1991, The Journal of biological chemistry.

[22]  L. Greene,et al.  Nerve growth factor and fibroblast growth factor selectively activate a protein kinase that phosphorylates high molecular weight microtubule-associated proteins. Detection, partial purification, and characterization in PC12 cells. , 1990, The Journal of biological chemistry.

[23]  Nancy Y. Ip,et al.  ERKs: A family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF , 1991, Cell.

[24]  J. Maller,et al.  Requirement for integration of signals from two distinct phosphorylation pathways for activation of MAP kinase , 1990, Nature.

[25]  J. Maller,et al.  Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II , 1988, Nature.

[26]  K. Takishima,et al.  Epidermal growth factor (EGF) receptor T669 peptide kinase from 3T3-L1 cells is an EGF-stimulated "MAP" kinase. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Weber,et al.  Complexes of Ras.GTP with Raf-1 and mitogen-activated protein kinase kinase. , 1993, Science.

[28]  R. Huber,et al.  Phosphotransferase and substrate binding mechanism of the cAMP‐dependent protein kinase catalytic subunit from porcine heart as deduced from the 2.0 A structure of the complex with Mn2+ adenylyl imidodiphosphate and inhibitor peptide PKI(5‐24). , 1993, The EMBO journal.

[29]  S. Sprang,et al.  Structural basis for the activation of glycogen phosphorylase b by adenosine monophosphate. , 1991, Science.

[30]  M. Cobb,et al.  Extracellular signal-regulated kinases: ERKs in progress. , 1991, Cell regulation.

[31]  M. Cobb,et al.  MAP kinases ERK1 and ERK2: pleiotropic enzymes in a ubiquitous signaling network. , 1994, Advances in cancer research.

[32]  T. Hunter,et al.  The protein kinase family: conserved features and deduced phylogeny of the catalytic domains. , 1988, Science.

[33]  D R Alessi,et al.  The human CL100 gene encodes a Tyr/Thr-protein phosphatase which potently and specifically inactivates MAP kinase and suppresses its activation by oncogenic ras in Xenopus oocyte extracts. , 1993, Oncogene.

[34]  E. Krebs,et al.  Microtubule-associated protein 2 kinases, ERK1 and ERK2, undergo autophosphorylation on both tyrosine and threonine residues: implications for their mechanism of activation. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[35]  E. Krebs,et al.  Multiple components in an epidermal growth factor-stimulated protein kinase cascade. In vitro activation of a myelin basic protein/microtubule-associated protein 2 kinase. , 1991, The Journal of biological chemistry.

[36]  M. Mumby,et al.  The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation , 1993, Cell.

[37]  T. Sturgill,et al.  Rapid stimulation by insulin of a serine/threonine kinase in 3T3-L1 adipocytes that phosphorylates microtubule-associated protein 2 in vitro. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[38]  R. Davis,et al.  Isolation and characterization of two growth factor-stimulated protein kinases that phosphorylate the epidermal growth factor receptor at threonine 669. , 1991, The Journal of biological chemistry.

[39]  C. Crews,et al.  The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. , 1992, Science.

[40]  A. Sharrocks,et al.  Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter , 1992, Nature.

[41]  J. Zheng,et al.  Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. , 1991, Science.

[42]  James R. Woodgett,et al.  Phosphorylation of c-jun mediated by MAP kinases , 1991, Nature.

[43]  Mike Carson,et al.  Ribbon models of macromolecules , 1987 .

[44]  Sung-Hou Kim,et al.  Crystal structure of cyclin-dependent kinase 2 , 1993, Nature.

[45]  H. Michel,et al.  Identification of Tyr-185 as the site of tyrosine autophosphorylation of recombinant mitogen-activated protein kinase p42mapk. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[46]  T. Steitz,et al.  Glucose-induced conformational change in yeast hexokinase. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[47]  Georg E. Schulz,et al.  Domain motions in proteins , 1991, Current Biology.

[48]  M. Karplus,et al.  Crystallographic R Factor Refinement by Molecular Dynamics , 1987, Science.

[49]  Susan S. Taylor,et al.  A template for the protein kinase family. , 1993, Trends in biochemical sciences.

[50]  J. Zheng,et al.  Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. , 1991, Science.

[51]  P. Blackshear,et al.  Evidence that extracellular signal-regulated kinases are the insulin-activated Raf-1 kinase kinases. , 1992, The Journal of biological chemistry.

[52]  E. Krebs,et al.  Isolation of cDNA clones coding for the catalytic subunit of mouse cAMP-dependent protein kinase. , 1986, Proceedings of the National Academy of Sciences of the United States of America.