1. Biochemistry and Chemical Biology
  2. Evolutionary Biology
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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
Research Article
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Cite this article as: eLife 2014;3:e04126 doi: 10.7554/eLife.04126

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.

Article and author information

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.

Reviewing Editor

  1. James Ferrell, Stanford University, United States

Publication history

  1. Received: July 23, 2014
  2. Accepted: October 9, 2014
  3. Accepted Manuscript published: October 13, 2014 (version 1)
  4. Accepted Manuscript updated: October 14, 2014 (version 2)
  5. Version of Record published: November 12, 2014 (version 3)
  6. Version of Record updated: April 29, 2016 (version 4)
  7. Version of Record updated: August 5, 2016 (version 5)

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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