Molecular basis of MAP kinase regulation

Protein Sci. 2013 Dec;22(12):1698-710. doi: 10.1002/pro.2374. Epub 2013 Oct 19.


Mitogen-activated protein kinases (MAPKs; ERK1/2, p38, JNK, and ERK5) have evolved to transduce environmental and developmental signals (growth factors, stress) into adaptive and programmed responses (differentiation, inflammation, apoptosis). Almost 20 years ago, it was discovered that MAPKs contain a docking site in the C-terminal lobe that binds a conserved 13-16 amino acid sequence known as the D- or KIM-motif (kinase interaction motif). Recent crystal structures of MAPK:KIM-peptide complexes are leading to a precise understanding of how KIM sequences contribute to MAPK selectivity. In addition, new crystal and especially NMR studies are revealing how residues outside the canonical KIM motif interact with specific MAPKs and contribute further to MAPK selectivity and signaling pathway fidelity. In this review, we focus on these recent studies, with an emphasis on the use of NMR spectroscopy, isothermal titration calorimetry and small angle X-ray scattering to investigate these processes.

Keywords: D-motif; DUSP; ERK; JNK; KIM; MAP kinase; NMR; PTP; SAXS; kinase interaction motif; p38; structure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Motifs*
  • Animals
  • Binding Sites
  • Consensus Sequence
  • Gene Expression Regulation
  • Humans
  • Mitogen-Activated Protein Kinase Kinases / chemistry*
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • Nuclear Magnetic Resonance, Biomolecular
  • Scattering, Small Angle
  • Sequence Analysis, Protein
  • Signal Transduction
  • Substrate Specificity
  • X-Ray Diffraction


  • Mitogen-Activated Protein Kinase Kinases