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Mechanism of ADP-ribosylation removal revealed by the structure and ligand complexes of the dimanganese mono-ADP-ribosylhydrolase DraG
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.
2009 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 106, no 34, 14247-14252 p.Article in journal (Refereed) Published
Abstract [en]

ADP-ribosylation is a ubiquitous regulatory posttranslational modification involved in numerous key processes such as DNA repair, transcription, cell differentiation, apoptosis, and the pathogenic mechanism of certain bacterial toxins. Despite the importance of this reversible process, very little is known about the structure and mechanism of the hydrolases that catalyze removal of the ADP-ribose moiety. In the phototrophic bacterium Rhodospirillum rubrum, dinitrogenase reductase-activating glycohydrolase (DraG), a dimanganese enzyme that reversibly associates with the cell membrane, is a key player in the regulation of nitrogenase activity. DraG has long served as a model protein for ADP-ribosylhydrolases. Here, we present the crystal structure of DraG in the holo and ADP-ribose bound forms. We also present the structure of a reaction intermediate analogue and propose a detailed catalytic mechanism for protein de-ADP-ribosylation involving ring opening of the substrate ribose. In addition, the particular manganese coordination in DraG suggests a rationale for the enzyme's preference for manganese over magnesium, although not requiring a redox active metal for the reaction.

Place, publisher, year, edition, pages
2009. Vol. 106, no 34, 14247-14252 p.
Identifiers
URN: urn:nbn:se:su:diva-29612DOI: 10.1073/pnas.0905906106ISI: 000269295100017OAI: oai:DiVA.org:su-29612DiVA: diva2:234461
Available from: 2009-09-08 Created: 2009-09-08 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Metabolic regulation of nitrogen fixation in Rhodospirillum rubrum
Open this publication in new window or tab >>Metabolic regulation of nitrogen fixation in Rhodospirillum rubrum
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Nitrogen, along with carbon, hydrogen and oxygen, is amongst the most abundant elements in all living cells. The capability to convert atmospheric dinitrogen to biologically usable nitrogen compounds is only found in some prokaryotes. Biological nitrogen fixation, the reduction of dinitrogen to ammonia, is the entry step into the global nitrogen cycle. Nitrogenase, the enzyme responsible for dinitrogen reduction, requires large amounts of ATP and reducing equivalents. Consequently, the nitrogen fixation process is subjected to sophisticated regulatory networks that respond to multiple environmental stimuli. In the free-living photosynthetic nitrogen-fixing bacterium Rhodospirillum rubrum, the activity of nitrogenase is tightly regulated at the post-translational level by reversible ADP-ribosylation in response to cellular changes in nitrogen and energy status, the so-called “switch-off” effect. Our studies have been focused on identifying the intracellular signal(s) and protein components acting during “switch-off”, and elucidating the mechanism underlying this regulation. We have shown that PII signal transduction proteins and the ammonium transporter AmtB1 play central roles in the signal transduction pathway leading to the post-translational regulation of nitrogenase, in particular, the involvement of AmtB1-PII complex formation during ammonium “switch-off”. In contrast, a different signaling pathway is operating during the energy “switch-off”, and several interesting differences are highlighted here. In addition, we have solved a high-resolution structure of Dinitrogenase Reductase Activating Glycohydrolase (DRAG) using X-ray crystallography. A detailed mechanism of ADP-ribose removal by DRAG is proposed, with our structural and functional studies on DRAG supporting a reversible membrane association mechanism of regulating its activity, further controlling the activity of nitrogenase.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2009. 64 p.
Keyword
Rhodospirillum rubrum, nitrogen fixation, switch-off, PII, AmtB1, DRAG
National Category
Dentistry
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-29404 (URN)978-91-7155-920-3 (ISBN)
Public defence
2009-10-02, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (English)
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Note
At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Submitted. Paper 4: Submitted.Available from: 2009-09-10 Created: 2009-08-26 Last updated: 2009-09-08Bibliographically approved

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Berthold, Catrine L.Wang, HeNordlund, StefanHögbom, Martin
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