Solution structure of ERK2 binding domain of MAPK phosphatase MKP-3: structural insights into MKP-3 activation by ERK2

Mol Cell. 2001 Feb;7(2):387-99. doi: 10.1016/s1097-2765(01)00186-1.


MAP kinases (MAPKs), which control mitogenic signal transduction in all eukaryotic organisms, are inactivated by dual specificity MAPK phosphatases (MKPs). MKP-3, a prototypical MKP, achieves substrate specificity through its N-terminal domain binding to the MAPK ERK2, resulting in the activation of its C-terminal phosphatase domain. The solution structure and biochemical analysis of the ERK2 binding (EB) domain of MKP-3 show that regions that are essential for ERK2 binding partly overlap with its sites that interact with the C-terminal catalytic domain, and that these interactions are functionally coupled to the active site residues of MKP-3. Our findings suggest a novel mechanism by which the EB domain binding to ERK2 is transduced to cause a conformational change of the C-terminal catalytic domain, resulting in the enzymatic activation of MKP-3.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Blotting, Western
  • Catalytic Domain
  • Dual Specificity Phosphatase 6
  • Enzyme Activation
  • Humans
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Models, Biological
  • Models, Molecular
  • Molecular Sequence Data
  • Mutagenesis
  • Nuclear Magnetic Resonance, Biomolecular
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Protein Tyrosine Phosphatases / chemistry*
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / metabolism*
  • Recombinant Fusion Proteins / metabolism
  • Sequence Alignment
  • Static Electricity


  • Recombinant Fusion Proteins
  • Mitogen-Activated Protein Kinase 1
  • DUSP6 protein, human
  • Dual Specificity Phosphatase 6
  • Protein Tyrosine Phosphatases

Associated data

  • PDB/1HZM