title: The yin-yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF.
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.
authors.affiliation: 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.
authors.forename: Christina
authors.initials: C
authors.lastname: Kiel
authors.affiliation: 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.
authors.forename: Hannah
authors.initials: H
authors.lastname: Benisty
authors.affiliation: 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.
authors.forename: Veronica
authors.identifier: http://orcid.org/0000-0002-0860-5990
authors.initials: V
authors.lastname: Lloréns-Rico
authors.affiliation: 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.
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
mesh_terms: D019943:Amino Acid Substitution; D002478:Cells, Cultured; D019295:Computational Biology; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D059645:Mutation Rate; D017354:Point Mutation; D011487:Protein Conformation; D017510:Protein Folding; D055550:Protein Stability; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D048493:Proto-Oncogene Proteins B-raf
keywords: biophysics; computational biology; genotype-phenotype association; human; passenger and driver mutations; structural biology; structure-energy calculations; systems biology