Ancestral resurrection reveals evolutionary mechanisms of kinase plasticity

Protein kinases have evolved diverse specificities to enable cellular information processing. To gain insight into the mechanisms underlying kinase diversification, we studied the CMGC protein kinases using ancestral reconstruction. Within this group, the cyclin dependent kinases (CDKs) and mitogen...

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Bibliographic Details
Published in:eLife 2014-10, Vol.3
Main Authors: Howard, Conor J, Hanson-Smith, Victor, Kennedy, Kristopher J, Miller, Chad J, Lou, Hua Jane, Johnson, Alexander D, Turk, Benjamin E, Holt, Liam J
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino acids
ancestral reconstruction
Animals
Arginine
Arginine - metabolism
Biochemistry
Biology
Cell division
cyclin-dependent kinase
Cyclins - metabolism
Divergence
Evolution
Evolution, Molecular
Genomics and Evolutionary Biology
Humans
Ime2
Information processing
Kinases
Kinetics
Mammals
Meiosis
Molecular Sequence Data
Mutation
Peptides - chemistry
Peptides - metabolism
phosphoregulatory network
Phosphorylation
Phylogeny
Proline
Proline - metabolism
protein kinase
Protein Kinases - metabolism
Proteins
Saccharomyces cerevisiae - cytology
Saccharomyces cerevisiae - enzymology
Software packages
Substrate Specificity
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Summary:Protein kinases have evolved diverse specificities to enable cellular information processing. To gain insight into the mechanisms underlying kinase diversification, we studied the CMGC protein kinases using ancestral reconstruction. Within this group, the cyclin dependent kinases (CDKs) and mitogen activated protein kinases (MAPKs) require proline at the +1 position of their substrates, while Ime2 prefers arginine. The resurrected common ancestor of CDKs, MAPKs, and Ime2 could phosphorylate substrates with +1 proline or arginine, with preference for proline. This specificity changed to a strong preference for +1 arginine in the lineage leading to Ime2 via an intermediate with equal specificity for proline and arginine. Mutant analysis revealed that a variable residue within the kinase catalytic cleft, DFGx, modulates +1 specificity. Expansion of Ime2 kinase specificity by mutation of this residue did not cause dominant deleterious effects in vivo. Tolerance of cells to new specificities likely enabled the evolutionary divergence of kinases.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.04126