Effect of BET missense mutations on bromodomain function, inhibitor binding and stability
Lysine acetylation is an important epigenetic mark regulating gene transcription and chromatin structure. Acetylated lysine residues are specifically recognized by bromodomains, small protein interaction modules that read these modification in a sequence and acetylation dependent way regulating the...
| Main Authors: | , , , , , , , |
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| Other Authors: | |
| Format: | Journal article |
| Language: | English |
| Published: |
Public Library of Science
2016
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| _version_ | 1797087937204060160 |
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| author | Lori, L Pasquo, A Lori, C Petrosino, M Chiaraluce, R Tallant, C Knapp, S Consalvi, V |
| author2 | Kashanchi, F |
| author_facet | Kashanchi, F Lori, L Pasquo, A Lori, C Petrosino, M Chiaraluce, R Tallant, C Knapp, S Consalvi, V |
| author_sort | Lori, L |
| collection | OXFORD |
| description | Lysine acetylation is an important epigenetic mark regulating gene transcription and chromatin structure. Acetylated lysine residues are specifically recognized by bromodomains, small protein interaction modules that read these modification in a sequence and acetylation dependent way regulating the recruitment of transcriptional regulators and chromatin remodelling enzymes to acetylated sites in chromatin. Recent studies revealed that bromodomains are highly druggable protein interaction domains resulting in the development of a large number of bromodomain inhibitors. BET bromodomain inhibitors received a lot of attention in the oncology field resulting in the rapid translation of early BET bromodomain inhibitors into clinical studies. Here we investigated the effects of mutations present as polymorphism or found in cancer on BET bromodomain function and stability and the influence of these mutants on inhibitor binding. We found that most BET missense mutations localize to peripheral residues in the two terminal helices. Crystal structures showed that the three dimensional structure is not compromised by these mutations but mutations located in close proximity to the acetyl-lysine binding site modulate acetyl-lysine and inhibitor binding. Most mutations affect significantly protein stability and tertiary structure in solution, suggesting new interactions and an alternative network of protein-protein interconnection as a consequence of single amino acid substitution. To our knowledge this is the first report studying the effect of mutations on bromodomain function and inhibitor binding. |
| first_indexed | 2024-03-07T02:42:41Z |
| format | Journal article |
| id | oxford-uuid:aafc9bb5-ea72-46d3-9936-e1b58750b4d0 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:42:41Z |
| publishDate | 2016 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | oxford-uuid:aafc9bb5-ea72-46d3-9936-e1b58750b4d02022-03-27T03:18:53ZEffect of BET missense mutations on bromodomain function, inhibitor binding and stabilityJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:aafc9bb5-ea72-46d3-9936-e1b58750b4d0EnglishSymplectic Elements at OxfordPublic Library of Science2016Lori, LPasquo, ALori, CPetrosino, MChiaraluce, RTallant, CKnapp, SConsalvi, VKashanchi, FLysine acetylation is an important epigenetic mark regulating gene transcription and chromatin structure. Acetylated lysine residues are specifically recognized by bromodomains, small protein interaction modules that read these modification in a sequence and acetylation dependent way regulating the recruitment of transcriptional regulators and chromatin remodelling enzymes to acetylated sites in chromatin. Recent studies revealed that bromodomains are highly druggable protein interaction domains resulting in the development of a large number of bromodomain inhibitors. BET bromodomain inhibitors received a lot of attention in the oncology field resulting in the rapid translation of early BET bromodomain inhibitors into clinical studies. Here we investigated the effects of mutations present as polymorphism or found in cancer on BET bromodomain function and stability and the influence of these mutants on inhibitor binding. We found that most BET missense mutations localize to peripheral residues in the two terminal helices. Crystal structures showed that the three dimensional structure is not compromised by these mutations but mutations located in close proximity to the acetyl-lysine binding site modulate acetyl-lysine and inhibitor binding. Most mutations affect significantly protein stability and tertiary structure in solution, suggesting new interactions and an alternative network of protein-protein interconnection as a consequence of single amino acid substitution. To our knowledge this is the first report studying the effect of mutations on bromodomain function and inhibitor binding. |
| spellingShingle | Lori, L Pasquo, A Lori, C Petrosino, M Chiaraluce, R Tallant, C Knapp, S Consalvi, V Effect of BET missense mutations on bromodomain function, inhibitor binding and stability |
| title | Effect of BET missense mutations on bromodomain function, inhibitor binding and stability |
| title_full | Effect of BET missense mutations on bromodomain function, inhibitor binding and stability |
| title_fullStr | Effect of BET missense mutations on bromodomain function, inhibitor binding and stability |
| title_full_unstemmed | Effect of BET missense mutations on bromodomain function, inhibitor binding and stability |
| title_short | Effect of BET missense mutations on bromodomain function, inhibitor binding and stability |
| title_sort | effect of bet missense mutations on bromodomain function inhibitor binding and stability |
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