1. Biochemistry and Chemical Biology
  2. Evolutionary Biology

Ancestral resurrection reveals evolutionary mechanisms of kinase plasticity

  1. Conor Howard
  2. Victor Hanson-Smith
  3. Kristopher J Kennedy
  4. Chad J Miller
  5. Hua Jane Lou
  6. Alexander D Johnson
  7. Benjamin Turk
  8. Liam J Holt  Is a corresponding author
  1. University of California Berkeley, United States
  2. University of California, San Francisco, United States
  3. Yale University School of Medicine, United States
  4. University of California San Francisco, United States
https://doi.org/10.7554/eLife.04126
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  1. Conor Howard
  2. Victor Hanson-Smith
  3. Kristopher J Kennedy
  4. Chad J Miller
  5. Hua Jane Lou
  6. Alexander D Johnson
  7. Benjamin Turk
  8. Liam J Holt
(2014)
Ancestral resurrection reveals evolutionary mechanisms of kinase plasticity
eLife 3:e04126.
https://doi.org/10.7554/eLife.04126
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Abstract

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.

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Author details

  1. Conor Howard

    University of California Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Victor Hanson-Smith

    University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  3. Kristopher J Kennedy

    University of California Berkeley, Berkeley, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Chad J Miller

    Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. Hua Jane Lou

    Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Alexander D Johnson

    University of California San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.

  7. Benjamin Turk

    Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.

  8. Liam J Holt

    University of California Berkeley, Berkeley, United States
    For correspondence
    liamholt@berkeley.edu
    Competing interests
    The authors declare that no competing interests exist.

Copyright

© 2014, Howard et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Conor Howard
  2. Victor Hanson-Smith
  3. Kristopher J Kennedy
  4. Chad J Miller
  5. Hua Jane Lou
  6. Alexander D Johnson
  7. Benjamin Turk
  8. Liam J Holt
(2014)
Ancestral resurrection reveals evolutionary mechanisms of kinase plasticity
eLife 3:e04126.
https://doi.org/10.7554/eLife.04126

Share this article

https://doi.org/10.7554/eLife.04126

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    1. Biochemistry and Chemical Biology
    2. Evolutionary Biology

    Ancestral reconstruction reveals mechanisms of ERK regulatory evolution

    Dajun Sang, Sudarshan Pinglay ... Liam J Holt
    Research Advance

    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.