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N(6)-methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase Alkbh5
Alkbh5 catalyzes demethylation of the N(6)-methyladenosine (m(6)A), an epigenetic mark that controls several physiological processes including carcinogenesis and stem cell differentiation. The activity of Alkbh5 comprises two coupled reactions. The first reaction involves decarboxylation of α-ketogl...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for the Advancement of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373141/ https://www.ncbi.nlm.nih.gov/pubmed/34407931 http://dx.doi.org/10.1126/sciadv.abi8215 |
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author | Purslow, Jeffrey A. Nguyen, Trang T. Khatiwada, Balabhadra Singh, Aayushi Venditti, Vincenzo |
author_facet | Purslow, Jeffrey A. Nguyen, Trang T. Khatiwada, Balabhadra Singh, Aayushi Venditti, Vincenzo |
author_sort | Purslow, Jeffrey A. |
collection | PubMed |
description | Alkbh5 catalyzes demethylation of the N(6)-methyladenosine (m(6)A), an epigenetic mark that controls several physiological processes including carcinogenesis and stem cell differentiation. The activity of Alkbh5 comprises two coupled reactions. The first reaction involves decarboxylation of α-ketoglutarate (αKG) and formation of a Fe(4+)═O species. This oxyferryl intermediate oxidizes the m(6)A to reestablish the canonical base. Despite coupling between the two reactions being required for the correct Alkbh5 functioning, the mechanisms linking dioxygen activation to m(6)A binding are not fully understood. Here, we use solution NMR to investigate the structure and dynamics of apo and holo Alkbh5. We show that binding of m(6)A to Alkbh5 induces a metal-centered rearrangement of αKG that increases the exposed area of the metal, making it available for binding O(2). Our study reveals the molecular mechanisms underlying activation of Alkbh5, therefore opening new perspectives for the design of novel strategies to control gene expression and cancer progression. |
format | Online Article Text |
id | pubmed-8373141 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-83731412021-08-27 N(6)-methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase Alkbh5 Purslow, Jeffrey A. Nguyen, Trang T. Khatiwada, Balabhadra Singh, Aayushi Venditti, Vincenzo Sci Adv Research Articles Alkbh5 catalyzes demethylation of the N(6)-methyladenosine (m(6)A), an epigenetic mark that controls several physiological processes including carcinogenesis and stem cell differentiation. The activity of Alkbh5 comprises two coupled reactions. The first reaction involves decarboxylation of α-ketoglutarate (αKG) and formation of a Fe(4+)═O species. This oxyferryl intermediate oxidizes the m(6)A to reestablish the canonical base. Despite coupling between the two reactions being required for the correct Alkbh5 functioning, the mechanisms linking dioxygen activation to m(6)A binding are not fully understood. Here, we use solution NMR to investigate the structure and dynamics of apo and holo Alkbh5. We show that binding of m(6)A to Alkbh5 induces a metal-centered rearrangement of αKG that increases the exposed area of the metal, making it available for binding O(2). Our study reveals the molecular mechanisms underlying activation of Alkbh5, therefore opening new perspectives for the design of novel strategies to control gene expression and cancer progression. American Association for the Advancement of Science 2021-08-18 /pmc/articles/PMC8373141/ /pubmed/34407931 http://dx.doi.org/10.1126/sciadv.abi8215 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited. |
spellingShingle | Research Articles Purslow, Jeffrey A. Nguyen, Trang T. Khatiwada, Balabhadra Singh, Aayushi Venditti, Vincenzo N(6)-methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase Alkbh5 |
title | N(6)-methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase Alkbh5 |
title_full | N(6)-methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase Alkbh5 |
title_fullStr | N(6)-methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase Alkbh5 |
title_full_unstemmed | N(6)-methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase Alkbh5 |
title_short | N(6)-methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase Alkbh5 |
title_sort | n(6)-methyladenosine binding induces a metal-centered rearrangement that activates the human rna demethylase alkbh5 |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8373141/ https://www.ncbi.nlm.nih.gov/pubmed/34407931 http://dx.doi.org/10.1126/sciadv.abi8215 |
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