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Elife. 2016 Jan 8;5:e12814. doi: 10.7554/eLife.12814.

The yin-yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF.

Kiel C1,2,3, Benisty H1,2,3, Lloréns-Rico V1,2,3, Serrano L1,2,3,4.

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EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona, Spain.
Universitat Pompeu Fabra, Barcelona, Spain.
Barcelona Institute of Science and Technology, Barcelona, Spain.
Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.


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.


biophysics; computational biology; genotype-phenotype association; human; passenger and driver mutations; structural biology; structure-energy calculations; systems biology

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