E2~Ub conjugates regulate the kinase activity of Shigella effector OspG during pathogenesis |
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| Authors: | Jonathan N Pruneda Danielle L Swaney Judit Villén John D Scott Andrew W Stadnyk Isolde Le Trong Ronald E Stenkamp Rachel E Klevit John R Rohde Peter S Brzovic |
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| Affiliation: | 1. Department of Biochemistry, University of Washington, Seattle, WA, USA;2. Department of Genome Sciences, University of Washington, Seattle, WA, USA;3. Howard Hughes Medical Institute, Department of Pharmacology, University of Washington, Seattle, WA, USA;4. Department of Pediatrics, Dalhousie University, Halifax, NS, Canada;5. Department of Biological Structure, University of Washington, Seattle, WA, USA;6. Department of Microbiology and Immunology, Dalhousie University, Halifax, NS, Canada |
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| Abstract: | Pathogenic bacteria introduce effector proteins directly into the cytosol of eukaryotic cells to promote invasion and colonization. OspG, a Shigella spp. effector kinase, plays a role in this process by helping to suppress the host inflammatory response. OspG has been reported to bind host E2 ubiquitin‐conjugating enzymes activated with ubiquitin (E2~Ub), a key enzyme complex in ubiquitin transfer pathways. A co‐crystal structure of the OspG/UbcH5c~Ub complex reveals that complex formation has important ramifications for the activity of both OspG and the UbcH5c~Ub conjugate. OspG is a minimal kinase domain containing only essential elements required for catalysis. UbcH5c~Ub binding stabilizes an active conformation of the kinase, greatly enhancing OspG kinase activity. In contrast, interaction with OspG stabilizes an extended, less reactive form of UbcH5c~Ub. Recognizing conserved E2 features, OspG can interact with at least ten distinct human E2s~Ub. Mouse oral infection studies indicate that E2~Ub conjugates act as novel regulators of OspG effector kinase function in eukaryotic host cells. |
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| Keywords: | bacterial effector E2 Ub‐conjugating enzyme kinase
Shigella
ubiquitin |
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