Allosteric enhancement of MAP kinase p38α's activity and substrate selectivity by docking interactions

Nat Struct Mol Biol. 2014 Aug;21(8):704-11. doi: 10.1038/nsmb.2861. Epub 2014 Jul 20.


Mitogen-activated protein kinases (MAPKs) are essential to intracellular signal transduction. MAPKs anchor their pathway-specific substrates through so-called 'docking interactions' at locations distal from the active site. Docking interactions ensure efficient substrate recognition, but their contribution to the kinase reaction itself remains unclear. Herein, we use solution NMR to analyze the interaction between dually phosphorylated, active human p38α and the C-terminal fragments of its substrate MK2. p38α phosphorylation and ATP loading collaboratively induce the active conformation; subsequently, p38α accommodates MK2 phosphoacceptor residues in its active site. The docking interaction enhances binding of ATP and the phosphoacceptor to p38α, accelerating the phosphotransfer reaction. Thus, the docking interaction enhances p38α's enzymatic activity toward pathway-specific substrates allosterically as well as by the anchor effect. These findings clarify how MAPK cascades are organized in cells, even under ATP-depleted conditions often associated with environmental stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenylyl Imidodiphosphate / chemistry
  • Allosteric Regulation
  • Apoenzymes / chemistry*
  • Catalytic Domain
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Mitogen-Activated Protein Kinase 14 / chemistry*
  • Molecular Docking Simulation
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptide Fragments / chemistry
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases / chemistry
  • Substrate Specificity


  • Apoenzymes
  • Intracellular Signaling Peptides and Proteins
  • Peptide Fragments
  • Adenylyl Imidodiphosphate
  • Adenosine Triphosphate
  • MAP-kinase-activated kinase 2
  • Protein-Serine-Threonine Kinases
  • Mitogen-Activated Protein Kinase 14