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Comparative structural analysis provides new insights into the function of R2-like ligand-binding oxidase
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0002-9527-9133
Stockholm University, Faculty of Science, Department of Biochemistry and Biophysics.ORCID iD: 0000-0002-0265-1873
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Number of Authors: 72022 (English)In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 596, no 12, p. 1600-1610Article in journal (Refereed) Published
Abstract [en]

R2-like ligand-binding oxidase (R2lox) is a ferritin-like protein that harbours a heterodinuclear manganese–iron active site. Although R2lox function is yet to be established, the enzyme binds a fatty acid ligand coordinating the metal centre and catalyses the formation of a tyrosine–valine ether cross-link in the protein scaffold upon O2 activation. Here, we characterized the ligands copurified with R2lox by mass spectrometry-based metabolomics. Moreover, we present the crystal structures of two new homologs of R2lox, from Saccharopolyspora erythraea and Sulfolobus acidocaldarius, at 1.38 Å and 2.26 Å resolution, respectively, providing the highest resolution structure for R2lox, as well as new insights into putative mechanisms regulating the function of the enzyme. 

Place, publisher, year, edition, pages
2022. Vol. 596, no 12, p. 1600-1610
Keywords [en]
aldehyde deformylating oxygenase, ferritin-like protein, hydroxy fatty acids, long-chain fatty acids, R2-like ligand-binding oxidase, R2lox
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:su:diva-203494DOI: 10.1002/1873-3468.14319ISI: 000764082200001PubMedID: 35175627Scopus ID: 2-s2.0-85126047671OAI: oai:DiVA.org:su-203494DiVA, id: diva2:1649565
Available from: 2022-04-04 Created: 2022-04-04 Last updated: 2022-08-05Bibliographically approved
In thesis
1. Shining light on unknown function proteins
Open this publication in new window or tab >>Shining light on unknown function proteins
2022 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The study of protein structure and function is a fundamental step for understanding biological systems and for creating a solid ground for future drug development. Despite the development of novel ground-breaking biochemical and bioinformatical tools in the last decades, most proteins found in nature still have unknown assigned function. In this thesis, I present four publications aimed at protein structure and function determination. In these publications we present one method for high-throughput condition screening of membrane proteins for structural studies and three publications that aim at contributing to the understanding of proteins found in the pathogenic bacterium Mycobacterium tuberculosis, the deadliest bacterium worldwide, responsible for over 1 million deaths every year. Membrane proteins are very important targets for drug development. However, the study of membrane proteins is much more complex than fortheir soluble counterpart. In paper I, we developed a high-throughput method for detergent screening of membrane proteins that significantly reduces the time needed to find optimal conditions for structural studies. We developed amethod that allows for the screening of 192 protein-detergent conditions in 3 days. We used a TEV-folding reporter GFP-His tag vector to be able to measure the stability and amount of each sample after detergent solubilization of the cell lysate.In paper II, we characterized the Mycobacterium smegmatis respiratory supercomplex accessory proteins AscF and AscG. AscF and AscG arelocated in close proximity to the D and K proton pathways of Cytochrome c oxidase and might play a regulatory role in the respiratory supercomplex. Wes how how AscF and AscG do not bind nor metals nor nucleotides, but that they are essential for the normal growth of the M. smegmatis. We also show that both proteins are highly conserved in almost whole Mycobacteriales families, including M. tuberculosis. In paper III, we present two novel structures of the ferritin-like protein R2lox and further characterize the co-purified ligands in its lipid-binding pocket. We demonstrate how the two prevalent ligands that co-purify with the enzyme are fatty acids that host a C12 hydroxy-group and a double bond between the hydroxy group and the carboxylic group. The new structures from Sulfolobus acidocaldarius and Saccharopolyspora erythraea reveal new information about the enzyme’s possible regulatory mechanism and its possible interaction with partner proteins. In paper IV, we performed structural and functional studies of nicotinamide adenine dinucleotide (NAD+) synthase (NadE), which performs the last step of the de novo synthesis of NAD+: the amidation of nicotinic acidadenine dinucleotide (NaAD) into NAD+. We showed that some prokaryotes concert up to three NadE isoforms depending on external ammonium (NH3) availability. During high external concentrations of NH3, the ammonium-dependent NadE acts as primary catalyst of NAD+ synthesis. However, two glutamine-dependent homologues are capable of deamidation of glutamine when external ammonium availability is reduced. We show how the octameric glutamine-dependent NadE is the principal catalyst during nitrogen-fixing conditions, while the dimeric variant is the primary catalyst when NH3 availability is limited.

Place, publisher, year, edition, pages
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2022. p. 56
Keywords
proteins, membrane proteins, metalloproteins, biochemistry, metabolism
National Category
Biochemistry Molecular Biology
Research subject
Biochemistry
Identifiers
urn:nbn:se:su:diva-203930 (URN)978-91-7911-874-7 (ISBN)978-91-7911-875-4 (ISBN)
Public defence
2022-06-02, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 09:00 (English)
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Available from: 2022-05-10 Created: 2022-04-15 Last updated: 2025-02-20Bibliographically approved

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Diamanti, RiccardoSrinivas, VivekLebrette, HugoHögbom, Martin

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