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A glutaredoxin domain fused to the radical-generating subunit of ribonucleotide reductase (RNR) functions as an efficient RNR reductant
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2018 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 293, no 41, p. 15889-15900Article in journal (Refereed) Published
Abstract [en]

Class I ribonucleotide reductase (RNR) consists of a catalytic subunit (NrdA) and a radical-generating subunit (NrdB) that together catalyze reduction of ribonucleotides to their corresponding deoxyribonucleotides. NrdB from the firmicute Facklamia ignava is a unique fusion protein with N-terminal add-ons of a glutaredoxin (Grx) domain followed by an ATP-binding domain, the ATP cone. Grx, usually encoded separately from the RNR operon, is a known RNR reductant. We show that the fused Grx domain functions as an efficient reductant of the F. ignava class I RNR via the common dithiol mechanism and, interestingly, also via a monothiol mechanism, although less efficiently. To our knowledge, a Grx that uses both of these two reaction mechanisms has not previously been observed with a native substrate. The ATP cone is in most RNRs an N-terminal domain of the catalytic subunit. It is an allosteric on/off switch promoting ribonucleotide reduction in the presence of ATP and inhibiting RNR activity in the presence of dATP. We found that dATP bound to the ATP cone of F. ignava NrdB promotes formation of tetramers that cannot form active complexes with NrdA. The ATP cone bound two dATP molecules but only one ATP molecule. F. ignava NrdB contains the recently identified radical-generating cofactor MnIII/MnIV. We show that NrdA from F. ignava can form a catalytically competent RNR with the MnIII/MnIV-containing NrdB from the flavobacterium Leeuwenhoekiella blandensis. In conclusion, F. ignava NrdB is fused with a Grx functioning as an RNR reductant and an ATP cone serving as an on/off switch.

Place, publisher, year, edition, pages
American Society for Biochemistry and Molecular Biology, 2018. Vol. 293, no 41, p. 15889-15900
Keywords [en]
ribonucleotide reductase, allosteric regulation, oxidation-reduction (redox), radical, manganese, ATP-cone, dATP inhibition, dithiol-monothiol, glutaredoxin, tetramers
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-153125DOI: 10.1074/jbc.RA118.004991ISI: 000447256000013PubMedID: 30166338OAI: oai:DiVA.org:umu-153125DiVA, id: diva2:1262487
Available from: 2018-11-12 Created: 2018-11-12 Last updated: 2018-11-12Bibliographically approved

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Hofer, Anders

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Hofer, AndersSjöberg, Britt-Marie
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