A conserved motif in JNK/p38-specific MAPK phosphatases as a determinant for JNK1 recognition and inactivation

Nat Commun. 2016 Mar 18:7:10879. doi: 10.1038/ncomms10879.

Abstract

Mitogen-activated protein kinases (MAPKs), important in a large array of signalling pathways, are tightly controlled by a cascade of protein kinases and by MAPK phosphatases (MKPs). MAPK signalling efficiency and specificity is modulated by protein-protein interactions between individual MAPKs and the docking motifs in cognate binding partners. Two types of docking interactions have been identified: D-motif-mediated interaction and FXF-docking interaction. Here we report the crystal structure of JNK1 bound to the catalytic domain of MKP7 at 2.4-Å resolution, providing high-resolution structural insight into the FXF-docking interaction. The (285)FNFL(288) segment in MKP7 directly binds to a hydrophobic site on JNK1 that is near the MAPK insertion and helix αG. Biochemical studies further reveal that this highly conserved structural motif is present in all members of the MKP family, and the interaction mode is universal and critical for the MKP-MAPK recognition and biological function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Amino Acid Sequence
  • Apoptosis / radiation effects
  • Biocatalysis
  • Catalytic Domain
  • Conserved Sequence*
  • Crystallography, X-Ray
  • DNA Mutational Analysis
  • Dual-Specificity Phosphatases / chemistry*
  • Dual-Specificity Phosphatases / metabolism*
  • Enzyme Activation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mitogen-Activated Protein Kinase 8 / chemistry
  • Mitogen-Activated Protein Kinase 8 / metabolism*
  • Mitogen-Activated Protein Kinase Phosphatases / chemistry*
  • Mitogen-Activated Protein Kinase Phosphatases / metabolism*
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Structure-Activity Relationship
  • Substrate Specificity
  • Ultraviolet Rays
  • p38 Mitogen-Activated Protein Kinases / metabolism*

Substances

  • Mitogen-Activated Protein Kinase 8
  • p38 Mitogen-Activated Protein Kinases
  • DUSP10 protein, human
  • Mitogen-Activated Protein Kinase Phosphatases
  • DUSP16 protein, human
  • Dual-Specificity Phosphatases