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

A Farooq1, G Chaturvedi, S Mujtaba

  • 1Structural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University, New York, NY 10029, USA.

Molecular Cell
|March 10, 2001
PubMed

Insights

Dual specificity MAPK phosphatases (MKPs) inactivate MAP kinases. MKP-3

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cell Signaling

Background:

  • Mitogenic signal transduction is controlled by MAP kinases (MAPKs) in eukaryotes.
  • Dual specificity MAPK phosphatases (MKPs) are key regulators that inactivate MAPKs.
  • MKP-3, a specific MKP, utilizes its N-terminal domain to bind MAPK ERK2, activating its C-terminal phosphatase domain.

Purpose of the Study:

  • To elucidate the structural and biochemical basis of MKP-3's substrate specificity and activation mechanism.
  • To investigate the interaction between the ERK2 binding (EB) domain of MKP-3 and its C-terminal catalytic domain.
  • To understand how ERK2 binding leads to enzymatic activation of MKP-3.

Main Methods:

  • Solution structure determination of the ERK2 binding (EB) domain of MKP-3.
  • Biochemical analysis of MKP-3 interactions.
  • Functional assays to assess enzymatic activity.

Main Results:

  • The EB domain of MKP-3 essential for ERK2 binding partially overlaps with sites interacting with the C-terminal catalytic domain.
  • These interactions are functionally coupled to the active site residues of MKP-3.
  • A novel mechanism for ERK2-mediated activation of MKP-3 is proposed.

Conclusions:

  • The EB domain's interaction with ERK2 induces conformational changes in the C-terminal catalytic domain.
  • This conformational change leads to the enzymatic activation of MKP-3.
  • Findings reveal a new regulatory mechanism for MKP-3 activity in signal transduction pathways.

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