N6-methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase Alkbh5

dc.contributor.author Purslow, Jeffrey
dc.contributor.author Nguyen, Trang
dc.contributor.author Khatiwada, Balabhadra
dc.contributor.author Singh, Aayushi
dc.contributor.author Venditti, Vincenzo
dc.contributor.department Chemistry
dc.date 2021-08-27T17:47:34.000
dc.date.accessioned 2021-09-09T16:37:57Z
dc.date.available 2021-09-09T16:37:57Z
dc.date.copyright Fri Jan 01 00:00:00 UTC 2021
dc.date.issued 2021-08-18
dc.description.abstract <p>Alkbh5 catalyzes demethylation of the <em>N</em>6-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.</p>
dc.description.comments <p>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." <em>Science Advances</em> 7, no. 34 (2021): eabi8215. DOI: <a href="https://dx.doi.org/10.1126/sciadv.abi8215" target="_blank">10.1126/sciadv.abi8215</a>. Posted with permission.</p>
dc.format.mimetype application/pdf
dc.identifier archive/lib.dr.iastate.edu/chem_pubs/1320/
dc.identifier.articleid 2325
dc.identifier.contextkey 24530564
dc.identifier.s3bucket isulib-bepress-aws-west
dc.identifier.submissionpath chem_pubs/1320
dc.identifier.uri https://dr.lib.iastate.edu/handle/20.500.12876/azJ4XKPv
dc.language.iso en
dc.source.bitstream archive/lib.dr.iastate.edu/chem_pubs/1320/2021_VendittiVincenzo_N6Methyladenosine.pdf|||Fri Jan 14 19:47:17 UTC 2022
dc.source.uri 10.1126/sciadv.abi8215
dc.subject.disciplines Biophysics
dc.title N6-methyladenosine binding induces a metal-centered rearrangement that activates the human RNA demethylase Alkbh5
dc.type article
dc.type.genre article
dspace.entity.type Publication
relation.isAuthorOfPublication 275c368b-2994-4c2e-98ae-c5c0af97640a
relation.isOrgUnitOfPublication 42864f6e-7a3d-4be3-8b5a-0ae3c3830a11
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