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Kinetic mechanism for p38 map kinase

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Overview

authors

  • LoGrasso, Philip
  • Frantz, B.
  • Rolando, A. M.
  • Okeefe, S. J.
  • Hermes, J. D.
  • Oneill, E. A.

publication date

  • 1997

journal

  • Biochemistry  Journal

abstract

  • p38 has been shown to be a critical enzyme in the pro-inflammatory cytokine pathway and is a member of the mitogen-activated protein (MAP) kinase family. While the details for p38 activation and subsequent signal transduction have begun to be elucidated, little is known about the kinetic mechanism for p38. In this study, we have determined the kinetic mechanism for p38 MAP kinase. Data from initial velocity patterns in the presence and absence of a dead-end inhibitor and two triarylimidazole p38 inhibitors were consistent with an ordered sequential mechanism for p38 with protein substrate, glutathione S-transferase-activating transcription factor 2 (GST-ATF2), binding before ATP. The ATP analog, adenylyl methylenediphosphonate (AMP-PCP), and two triarylimidazoles were competitive inhibitors versus ATP and uncompetitive inhibitors versus GST-ATF2. Equilibrium binding studies utilizing a tritiated ATP-competitive inhibitor were also consistent with this mechanism and suggest an inability of ATP to bind to p38 in the absence of protein substrate. Moreover, the Michaelis constant for GST-ATF2 was 12-fold greater than the dissociation constant, indicating that the binding of ATP affected the binding of GST-ATF2. An ordered sequential mechanism with protein substrate binding first is unique to p38 compared to cyclic AMP-dependent protein kinase (cAPK) and most tyrosine kinases and helps to explain the interaction between enzyme, substrates, and inhibitors.

subject areas

  • Activating Transcription Factor 2
  • Adenosine Triphosphate
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cloning, Molecular
  • Cyclic AMP Response Element-Binding Protein
  • Enzyme Inhibitors
  • Glutathione Transferase
  • Humans
  • Imidazoles
  • Kinetics
  • Mitogen-Activated Protein Kinases
  • Molecular Structure
  • Phosphorylation
  • Protein Binding
  • Pyridines
  • Recombinant Fusion Proteins
  • T-Lymphocytes
  • Transcription Factors
  • p38 Mitogen-Activated Protein Kinases
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Identity

International Standard Serial Number (ISSN)

  • 0006-2960

Digital Object Identifier (DOI)

  • 10.1021/bi9706778

PubMed ID

  • 9265622
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Additional Document Info

start page

  • 10422

end page

  • 10427

volume

  • 36

issue

  • 34

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