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

Ancestral reconstruction reveals mechanisms of ERK regulatory evolution.

Author information

1
Institute for Systems Genetics, New York University Langone Medical Center, New York, United States.
2
Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States.
3
Memorial Sloan Kettering Cancer Center, New York, United States.
4
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, United States.
5
Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, United States.
6
Department of Pharmacology, Yale University School of Medicine, New Haven, United States.

Abstract

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

PMID:
31407663
PMCID:
PMC6692128
DOI:
10.7554/eLife.38805
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