Oxidation of the Mycobacterium tuberculosis key virulence factor protein tyrosine phosphatase A (MptpA) reduces its phosphatase activity
- The Mycobacterium tuberculosis tyrosine-specific phosphatase MptpA and its cognate kinase PtkA are prospective targets for anti-tuberculosis drugs as they interact with the host defense response within the macrophages. Although both are structurally well-characterized, the functional mechanism regulating their activity remains poorly understood. Here, we investigate the effect of post-translational oxidation in regulating the function of MptpA. Treatment of MptpA with H2O2/NaHCO3, mimicking cellular oxidative stress conditions, leads to oxidation of the catalytic cysteine (C11) and to a conformational rearrangement of the phosphorylation loop (D-loop) by repositioning the conserved tyrosine 128 (Y128) and generating a temporarily inactive preclosed state of the phosphatase. Thus, the catalytic cysteine in the P-loop acts as a redox switch and regulates the phosphatase activity of MptpA.
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| Author: | Anna NiesterukGND, Sridhar SreeramuluORCiDGND, Hendrik R. A. JonkerORCiD, Christian RichterORCiDGND, Harald SchwalbeORCiDGND |
|---|---|
| URN: | urn:nbn:de:hebis:30:3-706087 |
| DOI: | https://doi.org/10.1002/1873-3468.14348 |
| ISSN: | 1873-3468 |
| Parent Title (English): | FEBS Letters |
| Publisher: | Wiley |
| Place of publication: | Chichester |
| Document Type: | Article |
| Language: | English |
| Date of Publication (online): | 2022/04/09 |
| Date of first Publication: | 2022/04/09 |
| Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
| Release Date: | 2023/10/12 |
| Tag: | Mycobacterium tuberculosis; cysteine-redox regulation; nuclear magnetic resonance spectroscopy; protein oxidation; protein tyrosine phosphatase; reactive oxygen species |
| Volume: | 596 |
| Issue: | 12 |
| Page Number: | 13 |
| First Page: | 1503 |
| Last Page: | 1515 |
| Note: | This work was supported in part by the DKTK (German Consortium for Translational Cancer Research), FOR2509 (German Research Foundation, DFG), and iNEXT-Discovery, project number 871037, funded by the Horizon 2020 program of the European Commission. The work at BMRZ was supported by the State of Hesse. |
| HeBIS-PPN: | 516390023 |
| Institutes: | Biochemie, Chemie und Pharmazie |
| Wissenschaftliche Zentren und koordinierte Programme / Zentrum für Biomolekulare Magnetische Resonanz (BMRZ) | |
| Dewey Decimal Classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
| 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit | |
| Sammlungen: | Universitätspublikationen |
| Licence (German): |  Creative Commons - CC BY - Namensnennung 4.0 International |
