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Diversity in Overall Activity Regulation of Ribonucleotide Reductase
Umeå University.
Stockholm University.
Umeå University.
Stockholm University. (Jarone Pinhassi)ORCID iD: 0000-0002-8779-6464
Show others and affiliations
2015 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, 1-24 p.Article in journal (Refereed) Published
Abstract [en]

Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to the corresponding deoxyribonucleotides, which are used as building blocks for DNA replication and repair. This process is tightly regulated via two allosteric sites, the specificity site (s-site) and the overall activity site (a-site). The a-site resides in an N-terminal ATP cone domain that binds dATP or ATP and functions as an on/off switch, whereas the composite s-site binds ATP, dATP, dTTP, or dGTP and determines which substrate to reduce. There are three classes of RNRs, and class I RNRs consist of different combinations of α and β subunits. In eukaryotic and Escherichia coli canonical class I RNRs, dATP inhibits enzyme activity through the formation of inactive α6 and α4β4 complexes, respectively. Here we show that the Pseudomonas aeruginosa class I RNR has a duplicated ATP cone domain and represents a third mechanism of overall activity regulation. Each α polypeptide binds three dATP molecules, and the N-terminal ATP cone is critical for binding two of the dATPs because a truncated protein lacking this cone could only bind one dATP to its s-site. ATP activates the enzyme solely by preventing dATP from binding. The dATP-induced inactive form is an α4 complex, which can interact with β2 to form a non-productive α4β2 complex. Other allosteric effectors induce a mixture of α2 and α4 forms, with the former being able to interact with β2 to form active α2β2 complexes. The unique features of the P. aeruginosa RNR are interesting both from evolutionary and drug discovery perspectives.

Place, publisher, year, edition, pages
2015. 1-24 p.
Keyword [en]
Allosteric Regulation, dATP inhibition, enzyme inactivation, oligomerization, overall activity regulation, protein complex, Pseudomonas aeruginosa (P. aeruginosa), Ribonucleotide Reductase
National Category
Biochemistry and Molecular Biology
Research subject
Natural Science, Chemistry
Identifiers
URN: urn:nbn:se:lnu:diva-50961DOI: 10.1074/jbc.M115.649624OAI: oai:DiVA.org:lnu-50961DiVA: diva2:912973
Available from: 2016-03-18 Created: 2016-03-17 Last updated: 2016-03-23Bibliographically approved

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CiteExportLink to record
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Citation style
  • apa
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