Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation
Intrinsically disordered proteins/regions (IDPs/IDRs) are proteins or peptide segments that fail to form stable 3-dimensional structures in the absence of partner proteins. They are abundant in eukaryotic proteomes and are often associated with human diseases, but their biological functions have bee...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
eLife Sciences Publications Ltd
2015-08-01
|
| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/07777 |
| _version_ | 1811201080843829248 |
|---|---|
| author | Zhengjian Zhang Zarko Boskovic Mahmud M Hussain Wenxin Hu Carla Inouye Han-Je Kim A Katherine Abole Mary K Doud Timothy A Lewis Angela N Koehler Stuart L Schreiber Robert Tjian |
| author_facet | Zhengjian Zhang Zarko Boskovic Mahmud M Hussain Wenxin Hu Carla Inouye Han-Je Kim A Katherine Abole Mary K Doud Timothy A Lewis Angela N Koehler Stuart L Schreiber Robert Tjian |
| author_sort | Zhengjian Zhang |
| collection | DOAJ |
| description | Intrinsically disordered proteins/regions (IDPs/IDRs) are proteins or peptide segments that fail to form stable 3-dimensional structures in the absence of partner proteins. They are abundant in eukaryotic proteomes and are often associated with human diseases, but their biological functions have been elusive to study. In this study, we report the identification of a tin(IV) oxochloride-derived cluster that binds an evolutionarily conserved IDR within the metazoan TFIID transcription complex. Binding arrests an isomerization of promoter-bound TFIID that is required for the engagement of Pol II during the first (de novo) round of transcription initiation. However, the specific chemical probe does not affect reinitiation, which requires the re-entry of Pol II, thus, mechanistically distinguishing these two modes of transcription initiation. This work also suggests a new avenue for targeting the elusive IDRs by harnessing certain features of metal-based complexes for mechanistic studies, and for the development of novel pharmaceutical interventions. |
| first_indexed | 2024-04-12T02:14:52Z |
| format | Article |
| id | doaj.art-b57824a678b743769a62a320c786ecfb |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:14:52Z |
| publishDate | 2015-08-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-b57824a678b743769a62a320c786ecfb2022-12-22T03:52:17ZengeLife Sciences Publications LtdeLife2050-084X2015-08-01410.7554/eLife.07777Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiationZhengjian Zhang0https://orcid.org/0000-0002-2840-0837Zarko Boskovic1Mahmud M Hussain2Wenxin Hu3Carla Inouye4Han-Je Kim5https://orcid.org/0000-0002-0305-259XA Katherine Abole6Mary K Doud7Timothy A Lewis8Angela N Koehler9Stuart L Schreiber10https://orcid.org/0000-0003-1922-7558Robert Tjian11Transcription Imaging Consortium, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United StatesDepartment of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States; Center for the Science of Therapeutics, Broad Institute, Cambridge, United StatesDepartment of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States; Center for the Science of Therapeutics, Broad Institute, Cambridge, United StatesTranscription Imaging Consortium, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United StatesLi Ka Shing Center for Biomedical and Health Sciences, Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United StatesCenter for the Science of Therapeutics, Broad Institute, Cambridge, United StatesDepartment of Chemistry, University of California, Berkeley, Berkeley, United StatesCenter for the Science of Therapeutics, Broad Institute, Cambridge, United StatesCenter for the Science of Therapeutics, Broad Institute, Cambridge, United StatesCenter for the Science of Therapeutics, Broad Institute, Cambridge, United States; David H. Koch Institute for Integrative Cancer Research, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United StatesDepartment of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States; Center for the Science of Therapeutics, Broad Institute, Cambridge, United StatesTranscription Imaging Consortium, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States; Li Ka Shing Center for Biomedical and Health Sciences, Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United StatesIntrinsically disordered proteins/regions (IDPs/IDRs) are proteins or peptide segments that fail to form stable 3-dimensional structures in the absence of partner proteins. They are abundant in eukaryotic proteomes and are often associated with human diseases, but their biological functions have been elusive to study. In this study, we report the identification of a tin(IV) oxochloride-derived cluster that binds an evolutionarily conserved IDR within the metazoan TFIID transcription complex. Binding arrests an isomerization of promoter-bound TFIID that is required for the engagement of Pol II during the first (de novo) round of transcription initiation. However, the specific chemical probe does not affect reinitiation, which requires the re-entry of Pol II, thus, mechanistically distinguishing these two modes of transcription initiation. This work also suggests a new avenue for targeting the elusive IDRs by harnessing certain features of metal-based complexes for mechanistic studies, and for the development of novel pharmaceutical interventions.https://elifesciences.org/articles/07777transcription factorintrinsically disordered proteins/regionsmetal oxo complexespreinitiation complexconformational isomerizationtranscription reinitiation |
| spellingShingle | Zhengjian Zhang Zarko Boskovic Mahmud M Hussain Wenxin Hu Carla Inouye Han-Je Kim A Katherine Abole Mary K Doud Timothy A Lewis Angela N Koehler Stuart L Schreiber Robert Tjian Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation eLife transcription factor intrinsically disordered proteins/regions metal oxo complexes preinitiation complex conformational isomerization transcription reinitiation |
| title | Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation |
| title_full | Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation |
| title_fullStr | Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation |
| title_full_unstemmed | Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation |
| title_short | Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation |
| title_sort | chemical perturbation of an intrinsically disordered region of tfiid distinguishes two modes of transcription initiation |
| topic | transcription factor intrinsically disordered proteins/regions metal oxo complexes preinitiation complex conformational isomerization transcription reinitiation |
| url | https://elifesciences.org/articles/07777 |
| work_keys_str_mv | AT zhengjianzhang chemicalperturbationofanintrinsicallydisorderedregionoftfiiddistinguishestwomodesoftranscriptioninitiation AT zarkoboskovic chemicalperturbationofanintrinsicallydisorderedregionoftfiiddistinguishestwomodesoftranscriptioninitiation AT mahmudmhussain chemicalperturbationofanintrinsicallydisorderedregionoftfiiddistinguishestwomodesoftranscriptioninitiation AT wenxinhu chemicalperturbationofanintrinsicallydisorderedregionoftfiiddistinguishestwomodesoftranscriptioninitiation AT carlainouye chemicalperturbationofanintrinsicallydisorderedregionoftfiiddistinguishestwomodesoftranscriptioninitiation AT hanjekim chemicalperturbationofanintrinsicallydisorderedregionoftfiiddistinguishestwomodesoftranscriptioninitiation AT akatherineabole chemicalperturbationofanintrinsicallydisorderedregionoftfiiddistinguishestwomodesoftranscriptioninitiation AT marykdoud chemicalperturbationofanintrinsicallydisorderedregionoftfiiddistinguishestwomodesoftranscriptioninitiation AT timothyalewis chemicalperturbationofanintrinsicallydisorderedregionoftfiiddistinguishestwomodesoftranscriptioninitiation AT angelankoehler chemicalperturbationofanintrinsicallydisorderedregionoftfiiddistinguishestwomodesoftranscriptioninitiation AT stuartlschreiber chemicalperturbationofanintrinsicallydisorderedregionoftfiiddistinguishestwomodesoftranscriptioninitiation AT roberttjian chemicalperturbationofanintrinsicallydisorderedregionoftfiiddistinguishestwomodesoftranscriptioninitiation |