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A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA
Productive transcriptional elongation of many cellular and viral mRNAs requires transcriptional factors to extract pTEFb from the 7SK snRNP by modulating the association between HEXIM and 7SK snRNA. In HIV-1, Tat binds to 7SK by displacing HEXIM. However, without the structure of the 7SK-HEXIM compl...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9378691/ https://www.ncbi.nlm.nih.gov/pubmed/35970937 http://dx.doi.org/10.1038/s42003-022-03734-w |
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author | Pham, Vincent V. Gao, Michael Meagher, Jennifer L. Smith, Janet L. D’Souza, Victoria M. |
author_facet | Pham, Vincent V. Gao, Michael Meagher, Jennifer L. Smith, Janet L. D’Souza, Victoria M. |
author_sort | Pham, Vincent V. |
collection | PubMed |
description | Productive transcriptional elongation of many cellular and viral mRNAs requires transcriptional factors to extract pTEFb from the 7SK snRNP by modulating the association between HEXIM and 7SK snRNA. In HIV-1, Tat binds to 7SK by displacing HEXIM. However, without the structure of the 7SK-HEXIM complex, the constraints that must be overcome for displacement remain unknown. Furthermore, while structure details of the Tat(NL4-3)-7SK complex have been elucidated, it is unclear how subtypes with more HEXIM-like Tat sequences accomplish displacement. Here we report the structures of HEXIM, Tat(G), and Tat(Fin) arginine rich motifs in complex with the apical stemloop-1 of 7SK. While most interactions between 7SK with HEXIM and Tat are similar, critical differences exist that guide function. First, the conformational plasticity of 7SK enables the formation of three different base pair configurations at a critical remodeling site, which allows for the modulation required for HEXIM binding and its subsequent displacement by Tat. Furthermore, the specific sequence variations observed in various Tat subtypes all converge on remodeling 7SK at this region. Second, we show that HEXIM primes its own displacement by causing specific local destabilization upon binding — a feature that is then exploited by Tat to bind 7SK more efficiently. |
format | Online Article Text |
id | pubmed-9378691 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-93786912022-08-17 A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA Pham, Vincent V. Gao, Michael Meagher, Jennifer L. Smith, Janet L. D’Souza, Victoria M. Commun Biol Article Productive transcriptional elongation of many cellular and viral mRNAs requires transcriptional factors to extract pTEFb from the 7SK snRNP by modulating the association between HEXIM and 7SK snRNA. In HIV-1, Tat binds to 7SK by displacing HEXIM. However, without the structure of the 7SK-HEXIM complex, the constraints that must be overcome for displacement remain unknown. Furthermore, while structure details of the Tat(NL4-3)-7SK complex have been elucidated, it is unclear how subtypes with more HEXIM-like Tat sequences accomplish displacement. Here we report the structures of HEXIM, Tat(G), and Tat(Fin) arginine rich motifs in complex with the apical stemloop-1 of 7SK. While most interactions between 7SK with HEXIM and Tat are similar, critical differences exist that guide function. First, the conformational plasticity of 7SK enables the formation of three different base pair configurations at a critical remodeling site, which allows for the modulation required for HEXIM binding and its subsequent displacement by Tat. Furthermore, the specific sequence variations observed in various Tat subtypes all converge on remodeling 7SK at this region. Second, we show that HEXIM primes its own displacement by causing specific local destabilization upon binding — a feature that is then exploited by Tat to bind 7SK more efficiently. Nature Publishing Group UK 2022-08-15 /pmc/articles/PMC9378691/ /pubmed/35970937 http://dx.doi.org/10.1038/s42003-022-03734-w Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Pham, Vincent V. Gao, Michael Meagher, Jennifer L. Smith, Janet L. D’Souza, Victoria M. A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA |
title | A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA |
title_full | A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA |
title_fullStr | A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA |
title_full_unstemmed | A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA |
title_short | A structure-based mechanism for displacement of the HEXIM adapter from 7SK small nuclear RNA |
title_sort | structure-based mechanism for displacement of the hexim adapter from 7sk small nuclear rna |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9378691/ https://www.ncbi.nlm.nih.gov/pubmed/35970937 http://dx.doi.org/10.1038/s42003-022-03734-w |
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