Campus Units

Chemistry, Biochemistry, Biophysics and Molecular Biology, Roy J. Carver Department of

Document Type

Article

Publication Version

Published Version

Publication Date

8-18-2021

Journal or Book Title

Science Advances

Volume

7

Issue

34

First Page

eabi8215

DOI

10.1126/sciadv.abi8215

Abstract

Alkbh5 catalyzes demethylation of the N6-methyladenosine (m6A), 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 Fe4+═O species. This oxyferryl intermediate oxidizes the m6A to reestablish the canonical base. Despite coupling between the two reactions being required for the correct Alkbh5 functioning, the mechanisms linking dioxygen activation to m6A 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 m6A to Alkbh5 induces a metal-centered rearrangement of αKG that increases the exposed area of the metal, making it available for binding O2. 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.

Comments

This article is published as Purslow, Jeffrey A., Trang T. Nguyen, Balabhadra Khatiwada, Aayushi Singh, and Vincenzo Venditti. "N6-methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase Alkbh5." Science Advances 7, no. 34 (2021): eabi8215. DOI: 10.1126/sciadv.abi8215. Posted with permission.

Creative Commons License

Creative Commons Attribution-NonCommercial 4.0 International License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Copyright Owner

The Authors

Language

en

File Format

application/pdf

Included in

Biophysics Commons

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