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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...

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Autores principales: Purslow, Jeffrey A., Nguyen, Trang T., Khatiwada, Balabhadra, Singh, Aayushi, Venditti, Vincenzo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
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.
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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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