The structure of mitogen-activated protein kinase p38 at 2.1-A resolution.

The structure of mitogen-activated protein (MAP) kinase p38 has been solved at 2.1-A to an R factor of 21.0%, making p38 the second low activity MAP kinase solved to date. Although p38 is topologically similar to the MAP kinase ERK2, the phosphorylation Lip (a regulatory loop near the active site) adopts a different fold in p38. The peptide substrate binding site and the ATP binding site are also different from those of ERK2. The results explain why MAP kinases are specific for different activating enzymes, substrates, and inhibitors. A model presented for substrate and activator interactions has implications for the evolution of protein kinase cascades.

[1]  R. Davis,et al.  MKK3- and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway , 1996, Molecular and cellular biology.

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

[3]  P. Kraulis.  A program to produce both detailed and schematic plots of protein structures , 1991 .

[4]  E. Goldsmith,et al.  Contributions of the Mitogen-activated Protein (MAP) Kinase Backbone and Phosphorylation Loop to MEK Specificity* , 1996, The Journal of Biological Chemistry.

[5]  S V Evans,et al.  SETOR: hardware-lighted three-dimensional solid model representations of macromolecules. , 1993, Journal of molecular graphics.

[6]  K. Irie,et al.  A Novel Kinase Cascade Mediated by Mitogen-activated Protein Kinase Kinase 6 and MKK3* , 1996, The Journal of Biological Chemistry.

[7]  Elizabeth J. Goldsmith,et al.  Atomic structure of the MAP kinase ERK2 at 2.3 Å resolution , 1994, Nature.

[8]  J. Shabanowitz,et al.  Identification of the regulatory phosphorylation sites in pp42/mitogen‐activated protein kinase (MAP kinase). , 1991, The EMBO journal.

[9]  R. Brent,et al.  Mxi2, a mitogen-activated protein kinase that recognizes and phosphorylates Max protein. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J. Greer.  Comparative modeling methods: Application to the family of the mammalian serine proteases , 1990, Proteins.

[11]  N. Jones,et al.  ATF‐2 contains a phosphorylation‐dependent transcriptional activation domain. , 1995, The EMBO journal.

[12]  Collaborative Computational,et al.  The CCP4 suite: programs for protein crystallography. , 1994, Acta crystallographica. Section D, Biological crystallography.

[13]  J. Thornton,et al.  PROCHECK: a program to check the stereochemical quality of protein structures , 1993 .

[14]  B. Kemp,et al.  Insights into autoregulation from the crystal structure of twitchin kinase , 1994, Nature.

[15]  J. Woodgett,et al.  Stress-activated protein kinases bind directly to the delta domain of c-Jun in resting cells: implications for repression of c-Jun function. , 1995, Oncogene.

[16]  I. Tsigelny,et al.  JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. , 1994, Genes & development.

[17]  Marc W. Kirschner,et al.  How Proteolysis Drives the Cell Cycle , 1996, Science.

[18]  Jiahuai Han,et al.  Characterization of the Structure and Function of a Novel MAP Kinase Kinase (MKK6) (*) , 1996, The Journal of Biological Chemistry.

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

[20]  R. Davis,et al.  MAP kinase binds to the NH2‐terminal activation domain of c‐Myc , 1994, FEBS letters.

[21]  Gaochao Zhou,et al.  Components of a New Human Protein Kinase Signal Transduction Pathway (*) , 1995, The Journal of Biological Chemistry.

[22]  A. Brunet,et al.  Identification of MAP Kinase Domains by Redirecting Stress Signals into Growth Factor Responses , 1996, Science.

[23]  Jerry L. Adams,et al.  A protein kinase involved in the regulation of inflammatory cytokine biosynthesis , 1994, Nature.

[24]  L Bibbs,et al.  A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. , 1994, Science.

[25]  J. Adams,et al.  Inhibitors of serine/threonine kinases. , 1995, Current opinion in biotechnology.

[26]  E. Goldsmith,et al.  Activity of the MAP kinase ERK2 is controlled by a flexible surface loop. , 1995, Structure.

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

[28]  B. Dérijard,et al.  Transcription factor ATF2 regulation by the JNK signal transduction pathway , 1995, Science.

[29]  K. Guan,et al.  Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2. , 1993, The Journal of biological chemistry.

[30]  D. Young,et al.  Cloning and Characterization of MEK6, a Novel Member of the Mitogen-activated Protein Kinase Kinase Cascade (*) , 1996, The Journal of Biological Chemistry.

[31]  M. Cobb,et al.  ERK3 Is a Constitutively Nuclear Protein Kinase (*) , 1996, The Journal of Biological Chemistry.

[32]  Xiaozhong Wang,et al.  Stress-Induced Phosphorylation and Activation of the Transcription Factor CHOP (GADD153) by p38 MAP Kinase , 1996, Science.

[33]  M. Cobb,et al.  Extracellular signal-regulated kinases 2 autophosphorylates on a subset of peptides phosphorylated in intact cells in response to insulin and nerve growth factor: analysis by peptide mapping. , 1992, Molecular biology of the cell.

[34]  S. Taylor,et al.  Domain movements in protein kinases. , 1994, Current opinion in structural biology.

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

[36]  L Meijer,et al.  Multiple modes of ligand recognition: Crystal structures of cyclin‐dependent protein kinase 2 in complex with ATP and two inhibitors, olomoucine and isopentenyladenine , 1995, Proteins.

[37]  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.

[38]  R. Read.  Improved Fourier Coefficients for Maps Using Phases from Partial Structures with Errors , 1986 .

[39]  J. Navaza,et al.  AMoRe: an automated package for molecular replacement , 1994 .

[40]  John C. Lee,et al.  Identification of Mitogen-activated Protein (MAP) Kinase-activated Protein Kinase-3, a Novel Substrate of CSBP p38 MAP Kinase (*) , 1996, The Journal of Biological Chemistry.

[41]  Jiahuai Han,et al.  Primary structure of BMK1: a new mammalian map kinase. , 1995, Biochemical and biophysical research communications.

[42]  M. Karin,et al.  JNK1: A protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain , 1994, Cell.

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

[44]  Sung-Hou Kim,et al.  Sparse matrix sampling: a screening method for crystallization of proteins , 1991 .

[45]  N. Ahn,et al.  Transformation of mammalian cells by constitutively active MAP kinase kinase. , 1994, Science.

[46]  Michel Morange,et al.  A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins , 1994, Cell.

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

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

[49]  S. Hubbard,et al.  Crystal structure of the tyrosine kinase domain of the human insulin receptor , 1994, Nature.

[50]  Jiahuai Han,et al.  Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms , 1995, Science.

[51]  A. Ullrich,et al.  ERK6, a mitogen-activated protein kinase involved in C2C12 myoblast differentiation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[52]  T. Curran,et al.  Pro-Leu-Ser/Thr-Pro is a consensus primary sequence for substrate protein phosphorylation. Characterization of the phosphorylation of c-myc and c-jun proteins by an epidermal growth factor receptor threonine 669 protein kinase. , 1991, The Journal of biological chemistry.

[53]  J. Hsuan,et al.  Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of hsp27 , 1994, Cell.

[54]  Jiahuai Han,et al.  Pro-inflammatory Cytokines and Environmental Stress Cause p38 Mitogen-activated Protein Kinase Activation by Dual Phosphorylation on Tyrosine and Threonine (*) , 1995, The Journal of Biological Chemistry.

[55]  L. Johnson,et al.  Active and Inactive Protein Kinases: Structural Basis for Regulation , 1996, Cell.

[56]  M. Karin,et al.  Identification of a dual specificity kinase that activates the Jun kinases and p38-Mpk2. , 1995, Science.

[57]  S H Kim,et al.  Structural basis for specificity and potency of a flavonoid inhibitor of human CDK2, a cell cycle kinase. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[58]  K. Longenecker,et al.  Three-dimensional structure of mammalian casein kinase I: molecular basis for phosphate recognition. , 1996, Journal of molecular biology.

[59]  P. Jeffrey,et al.  Structural basis of cyclin-dependent kinase activation by phosphorylation , 1996, Nature Structural Biology.