The yin-yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF
Mostra el registre complet Registre parcial de l'ítem
- dc.contributor.author Kiel, Christinaca
- dc.contributor.author Benisty, Hannah, 1986-ca
- dc.contributor.author Lloréns Rico, Verónica, 1989-ca
- dc.contributor.author Serrano Pubull, Luis, 1982-ca
- dc.date.accessioned 2016-06-03T15:01:51Z
- dc.date.available 2016-06-03T15:01:51Z
- dc.date.issued 2016
- dc.description.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.ca
- dc.description.sponsorship This work was funded by the EU (PRIMES under grant agreement number FP7-HEALTH-F4-2011-278568), the Spanish Ministerio de Economía y Competitividad, Plan Nacional BIO2012-39754, and the European Fund for Regional Development. We acknowledge support of the Spanish Ministerio de Economı´a y Competitividad for the ‘Centro de Excelencia Severo Ochoa 2013-2017’ (SEV-2012-0208).
- dc.format.mimetype application/pdfca
- dc.identifier.citation Kiel C, Benisty H, Lloréns-Rico V, Serrano L. The yin-yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF. Elife. 2016; 5: e12814. DOI 10.7554/eLife.12814ca
- dc.identifier.doi http://dx.doi.org/10.7554/eLife.12814
- dc.identifier.issn 2050-084X
- dc.identifier.uri http://hdl.handle.net/10230/26822
- dc.language.iso engca
- dc.publisher eLifeca
- dc.relation.ispartof Elife. 2016; 5: e12814
- dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SEV-2012-0208
- dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/278568
- dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BIO2012-39754
- dc.rights © Kiel et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.ca
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/ca
- dc.subject.keyword Biophysics
- dc.subject.keyword Computational biology
- dc.subject.keyword Genotype-phenotype association
- dc.subject.keyword Human
- dc.subject.keyword Passenger and driver mutations
- dc.subject.keyword Structural biology
- dc.subject.keyword Structure-energy calculations
- dc.subject.keyword Systems biology
- dc.subject.other Biologia computacionalca
- dc.title The yin-yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAFca
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/publishedVersionca