3 results on '"Haydyn D. T. Mertens"'
Search Results
2. Structural model of human dUTPase in complex with a novel proteinaceous inhibitor
- Author
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Judit Matejka, Antoni J. Borysik, Oliver Ozohanics, Kinga Nyíri, M.J. Harris, Károly Vékey, Dmitri I. Svergun, Gergely N. Nagy, Haydyn D. T. Mertens, Bianka Kőhegyi, Judit Szabó, Beáta G. Vértessy, Veronika Papp-Kádár, Borbála Tihanyi, and Veronika Németh-Pongrácz
- Subjects
0301 basic medicine ,Staphylococcus aureus ,Protein Conformation ,lcsh:Medicine ,Repressor ,Plasma protein binding ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Protein structure ,Bacterial Proteins ,X-Ray Diffraction ,Catalytic Domain ,Scattering, Small Angle ,Humans ,Pyrophosphatases ,lcsh:Science ,chemistry.chemical_classification ,Multidisciplinary ,biology ,Functional analysis ,lcsh:R ,Active site ,Staphylococcal Infections ,Deoxyuridine ,3. Good health ,Molecular Docking Simulation ,Repressor Proteins ,030104 developmental biology ,Enzyme ,chemistry ,030220 oncology & carcinogenesis ,biology.protein ,Biophysics ,lcsh:Q ,Protein Multimerization ,ddc:600 ,DNA ,Protein Binding - Abstract
Human deoxyuridine 5′-triphosphate nucleotidohydrolase (dUTPase), essential for DNA integrity, acts as a survival factor for tumor cells and is a target for cancer chemotherapy. Here we report that the Staphylococcal repressor protein StlSaPIBov1 (Stl) forms strong complex with human dUTPase. Functional analysis reveals that this interaction results in significant reduction of both dUTPase enzymatic activity and DNA binding capability of Stl. We conducted structural studies to understand the mechanism of this mutual inhibition. Small-angle X-ray scattering (SAXS) complemented with hydrogen-deuterium exchange mass spectrometry (HDX-MS) data allowed us to obtain 3D structural models comprising a trimeric dUTPase complexed with separate Stl monomers. These models thus reveal that upon dUTPase-Stl complex formation the functional homodimer of Stl repressor dissociates, which abolishes the DNA binding ability of the protein. Active site forming dUTPase segments were directly identified to be involved in the dUTPase-Stl interaction by HDX-MS, explaining the loss of dUTPase activity upon complexation. Our results provide key novel structural insights that pave the way for further applications of the first potent proteinaceous inhibitor of human dUTPase.
- Published
- 2018
3. Signaling ammonium across membranes through an ammonium sensor histidine kinase
- Author
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Susana L. A. Andrade, Haydyn D. T. Mertens, Vladimir Y. Lunin, Dmitri I. Svergun, Fabian Frank, Tobias Pflüger, Camila F. Hernández, Manfred W. Baumstark, Philipp Lewe, and Mike S. M. Jetten
- Subjects
Models, Molecular ,0301 basic medicine ,Histidine Kinase ,Science ,Protein domain ,General Physics and Astronomy ,Crystallography, X-Ray ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Bacterial Proteins ,Protein Domains ,X-Ray Diffraction ,Ammonium Compounds ,Scattering, Small Angle ,Ammonium ,Amino Acid Sequence ,Kinase activity ,lcsh:Science ,GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries) ,Histidine ,Binding Sites ,Multidisciplinary ,Bacteria ,Sequence Homology, Amino Acid ,Chemistry ,Cell Membrane ,Histidine kinase ,Membrane Transport Proteins ,General Chemistry ,3. Good health ,030104 developmental biology ,Anammox ,Ecological Microbiology ,Biophysics ,Phosphorylation ,lcsh:Q ,ddc:500 ,Signal transduction ,Oxidation-Reduction ,030217 neurology & neurosurgery ,Protein Binding ,Signal Transduction - Abstract
Sensing and uptake of external ammonium is essential for anaerobic ammonium-oxidizing (anammox) bacteria, and is typically the domain of the ubiquitous Amt/Rh ammonium transporters. Here, we report on the structure and function of an ammonium sensor/transducer from the anammox bacterium “Candidatus Kuenenia stuttgartiensis” that combines a membrane-integral ammonium transporter domain with a fused histidine kinase. It contains a high-affinity ammonium binding site not present in assimilatory Amt proteins. The levels of phosphorylated histidine in the kinase are coupled to the presence of ammonium, as conformational changes during signal recognition by the Amt module are transduced internally to modulate the kinase activity. The structural analysis of this ammonium sensor by X-ray crystallography and small-angle X-ray-scattering reveals a flexible, bipartite system that recruits a large uptake transporter as a sensory module and modulates its functionality to achieve a mechanistic coupling to a kinase domain in order to trigger downstream signaling events., For anammox bacteria, the sensing and uptake of ammonium is essential and specialized proteins, like Ks-Amt5, mediate such processes. Here, authors perform biophysical, biochemical, and structural analysis on Ks-Amt5 and establish a role for this protein as an ammonium-sensing signal transducer.
- Published
- 2018
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