The yin–yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF
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 trie...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-01-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/12814 |
| _version_ | 1797997651884507136 |
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| author | Christina Kiel Hannah Benisty Veronica Lloréns-Rico Luis Serrano |
| author_facet | Christina Kiel Hannah Benisty Veronica Lloréns-Rico Luis Serrano |
| author_sort | Christina Kiel |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T10:35:00Z |
| format | Article |
| id | doaj.art-d5a4d31184774cab8e3aec9f37cd21cd |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:35:00Z |
| publishDate | 2016-01-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d5a4d31184774cab8e3aec9f37cd21cd2022-12-22T04:29:18ZengeLife Sciences Publications LtdeLife2050-084X2016-01-01510.7554/eLife.12814The yin–yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAFChristina Kiel0Hannah Benisty1Veronica Lloréns-Rico2https://orcid.org/0000-0002-0860-5990Luis Serrano3EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; Barcelona Institute of Science and Technology, Barcelona, SpainEMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; Barcelona Institute of Science and Technology, Barcelona, SpainEMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation, Barcelona, Spain; Universitat Pompeu Fabra, Barcelona, Spain; Barcelona Institute of Science and Technology, Barcelona, SpainEMBL/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, SpainMany 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.https://elifesciences.org/articles/12814structure-energy calculationsgenotype-phenotype associationpassenger and driver mutations |
| spellingShingle | Christina Kiel Hannah Benisty Veronica Lloréns-Rico Luis Serrano The yin–yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF eLife structure-energy calculations genotype-phenotype association passenger and driver mutations |
| title | The yin–yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF |
| title_full | The yin–yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF |
| title_fullStr | The yin–yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF |
| title_full_unstemmed | The yin–yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF |
| title_short | The yin–yang of kinase activation and unfolding explains the peculiarity of Val600 in the activation segment of BRAF |
| title_sort | yin yang of kinase activation and unfolding explains the peculiarity of val600 in the activation segment of braf |
| topic | structure-energy calculations genotype-phenotype association passenger and driver mutations |
| url | https://elifesciences.org/articles/12814 |
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