Show simple item record

dc.contributor.authorMaggiolo, Ailiena O.
dc.contributor.authorThomas, William C.
dc.contributor.authorMeisburger, Steve P.
dc.contributor.authorBoal, Amie K.
dc.contributor.authorParker, Mackenzie James
dc.contributor.authorKim, Albert Dong Woo
dc.contributor.authorAndo, Nozomi
dc.contributor.authorStubbe, JoAnne
dc.date.accessioned2018-11-05T14:20:09Z
dc.date.available2018-11-05T14:20:09Z
dc.date.issued2018-04
dc.identifier.issn0027-8424
dc.identifier.issn1091-6490
dc.identifier.urihttp://hdl.handle.net/1721.1/118869
dc.description.abstract© 2018 National Academy of Sciences. All rights reserved. The high fidelity of DNA replication and repair is attributable, in part, to the allosteric regulation of ribonucleotide reductases (RNRs) that maintains proper deoxynucleotide pool sizes and ratios in vivo. In class Ia RNRs, ATP (stimulatory) and dATP (inhibitory) regulate activity by binding to the ATP-cone domain at the N terminus of the large α subunit and altering the enzyme’s quaternary structure. Class Ib RNRs, in contrast, have a partial cone domain and have generally been found to be insensitive to dATP inhibition. An exception is the Bacillus subtilis Ib RNR, which we recently reported to be inhibited by physiological concentrations of dATP. Here, we demonstrate that the α subunit of this RNR contains tightly bound deoxyadenosine 5′-monophosphate (dAMP) in its N-terminal domain and that dATP inhibition of CDP reduction is enhanced by its presence. X-ray crystallography reveals a previously unobserved (noncanonical) α2dimer with its entire interface composed of the partial N-terminal cone domains, each binding a dAMP molecule. Using small-angle X-ray scattering (SAXS), we show that this noncanonical α2dimer is the predominant form of the dAMP-bound α in solution and further show that addition of dATP leads to the formation of larger oligomers. Based on this information, we propose a model to describe the mechanism by which the noncanonical α2inhibits the activity of the B. subtilis Ib RNR in a dATP- and dAMP-dependent manner.en_US
dc.description.sponsorshipNational Science Foundation (U.S.) (grant NSF-0070319)en_US
dc.description.sponsorshipUnited States. Department of Energy. Office of Science (contract DE-AC02-06CH11357)en_US
dc.description.sponsorshipNational Cancer Institute (U.S.) (Grant ACB-12002)en_US
dc.description.sponsorshipNational Institute of General Medical Sciences (U.S.) (Grant AGM-12006)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.). Office of Research Infrastructure Programs (High-End Instrumentation Grant 1S10OD01 2289-01A1)en_US
dc.description.sponsorshipMichigan Economic Development Corporationen_US
dc.description.sponsorshipMichigan Technology Tri-Corridor (Grant 085P1000817)en_US
dc.description.sponsorshipUnited States. Department of Energy. Office of Science User Facility (Contract DE-AC02-05CH11231)en_US
dc.description.sponsorshipNational Science Foundation (U.S.) (grant DMR-1332208)en_US
dc.description.sponsorshipNational Institute of General Medical Sciences (U.S.) (Grant GM-10348)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant GM10008)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant GM1247)en_US
dc.description.sponsorshipNational Institutes of Health (U.S.) (grant GM081393)en_US
dc.description.sponsorshipPrinceton University (start-up funds)en_US
dc.publisherProceedings of the National Academy of Sciencesen_US
dc.relation.isversionofhttp://dx.doi.org/10.1073/PNAS.1800356115en_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.sourcePNASen_US
dc.titleAn endogenous dAMP ligand inen_US
dc.typeArticleen_US
dc.identifier.citationParker, Mackenzie J., Ailiena O. Maggiolo, William C. Thomas, Albert Kim, Steve P. Meisburger, Nozomi Ando, Amie K. Boal, and JoAnne Stubbe. “An Endogenous dAMP Ligand inBacillus Subtilisclass Ib RNR Promotes Assembly of a Noncanonical Dimer for Regulation by dATP.” Proceedings of the National Academy of Sciences 115, no. 20 (April 30, 2018): E4594–E4603.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Chemistryen_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Physicsen_US
dc.contributor.mitauthorParker, Mackenzie James
dc.contributor.mitauthorKim, Albert Dong Woo
dc.contributor.mitauthorAndo, Nozomi
dc.contributor.mitauthorStubbe, JoAnne
dc.relation.journalProceedings of the National Academy of Sciencesen_US
dc.eprint.versionFinal published versionen_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dc.date.updated2018-10-12T16:24:50Z
dspace.orderedauthorsParker, Mackenzie J.; Maggiolo, Ailiena O.; Thomas, William C.; Kim, Albert; Meisburger, Steve P.; Ando, Nozomi; Boal, Amie K.; Stubbe, JoAnneen_US
dspace.embargo.termsNen_US
dc.identifier.orcidhttps://orcid.org/0000-0001-7174-0485
dc.identifier.orcidhttps://orcid.org/0000-0001-8076-4489
mit.licensePUBLISHER_POLICYen_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record