Ancestral reconstruction reveals mechanisms of ERK regulatory evolution

Elife. 2019 Aug 13;8:e38805. doi: 10.7554/eLife.38805.


Protein kinases are crucial to coordinate cellular decisions and therefore their activities are strictly regulated. Previously we used ancestral reconstruction to determine how CMGC group kinase specificity evolved (Howard et al., 2014). In the present study, we reconstructed ancestral kinases to study the evolution of regulation, from the inferred ancestor of CDKs and MAPKs, to modern ERKs. Kinases switched from high to low autophosphorylation activity at the transition to the inferred ancestor of ERKs 1 and 2. Two synergistic amino acid changes were sufficient to induce this change: shortening of the β3-αC loop and mutation of the gatekeeper residue. Restoring these two mutations to their inferred ancestral state led to a loss of dependence of modern ERKs 1 and 2 on the upstream activating kinase MEK in human cells. Our results shed light on the evolutionary mechanisms that led to the tight regulation of a kinase that is central in development and disease.

Keywords: ancestral reconstruction; biochemistry; chemical biology; erk; evolution; evolutionary biology; extracellular regulated kinase; human; protein kinase.

Publication types

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

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Computational Biology
  • Evolution, Molecular*
  • Humans
  • MAP Kinase Signaling System / genetics*
  • Mutation, Missense
  • Phosphorylation
  • Protein Processing, Post-Translational