1. Structural Biology and Molecular Biophysics
  2. Computational and Systems Biology
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The yin-yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF

  1. Christina Kiel  Is a corresponding author
  2. Hannah Benisty
  3. Veronica Lloréns-Rico
  4. Luis Serrano
  1. Centre for Genomic Regulation, Spain
Research Article
  • Cited 18
  • Views 1,948
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Cite this article as: eLife 2016;5:e12814 doi: 10.7554/eLife.12814

Abstract

Many driver mutations in cancer are specific in that they occur at significantly higher rates than - presumably - functionally alternative mutations. For example, V600E in the BRAF hydrophobic activation segment (AS) pocket accounts for >95% of all kinase mutations. While many hypotheses tried to explain such significant mutation patterns, conclusive explanations are lacking. Here, we use experimental and in silico structure-energy statistical analyses, to elucidate why the V600E mutation, but no other mutation at this, or any other positions in BRAF's hydrophobic pocket, is predominant. We find that BRAF mutation frequencies depend on the equilibrium between the destabilization of the hydrophobic pocket, the overall folding energy, the activation of the kinase and the number of bases required to change the corresponding amino acid. Using a random forest classifier, we quantitatively dissected the parameters contributing to BRAF AS cancer frequencies. These findings can be applied to genome-wide association studies and prediction models.

Article and author information

Author details

  1. Christina Kiel

    EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona, Spain
    For correspondence
    christina.kiel@crg.eu
    Competing interests
    The authors declare that no competing interests exist.
  2. Hannah Benisty

    EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Veronica Lloréns-Rico

    EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  4. Luis Serrano

    EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Yibing Shan, DE Shaw Research, United States

Publication history

  1. Received: November 4, 2015
  2. Accepted: January 7, 2016
  3. Accepted Manuscript published: January 8, 2016 (version 1)
  4. Version of Record published: January 28, 2016 (version 2)

Copyright

© 2016, Kiel 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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