E2~Ub conjugates regulate the kinase activity of Shigella effector OspG during pathogenesis.

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.

• Authors: Jonathan N Pruneda, F Donelson Smith, Angela Daurie, 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
• Journal: The EMBO journal (EMBO J) Vol. 33 Issue 5 Pg. 437-49 (Mar 03 2014) ISSN: 1460-2075 [Electronic] England
• PMID: 24446487 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Ubiquitin
• Virulence Factors
• UBE2D3 protein, human
• Ubiquitin-Conjugating Enzymes
• Protein Kinases

Topics

• Animals
• Cell Line
• Crystallography, X-Ray
• Humans
• Mice
• Models, Molecular
• Protein Conformation
• Protein Kinases (chemistry, metabolism)
• Protein Multimerization
• Shigella flexneri (metabolism)
• Ubiquitin (chemistry, metabolism)
• Ubiquitin-Conjugating Enzymes (chemistry, metabolism)
• Virulence Factors (chemistry, metabolism)