E2~Ub conjugates regulate the kinase activity of Shigella effector OspG during pathogenesis.
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.
Department of Biochemistry, University of Washington, Seattle, WA, USA.
Jonathan N
JN
Pruneda
F Donelson
FD
Smith
Angela
A
Daurie
Danielle L
DL
Swaney
Judit
J
Villén
John D
JD
Scott
Andrew W
AW
Stadnyk
Isolde
I
Le Trong
Ronald E
RE
Stenkamp
Rachel E
RE
Klevit
John R
JR
Rohde
Peter S
PS
Brzovic
D000818:Animals; D002460:Cell Line; D018360:Crystallography, X-Ray; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D055503:Protein Multimerization; D012763:Shigella flexneri / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes / Q000737:chemistry / Q000378:metabolism*; D037521:Virulence Factors / Q000737:chemistry / Q000378:metabolism*
D025801:Ubiquitin; D037521:Virulence Factors; C097310:UBE2D3 protein, human; D044763:Ubiquitin-Conjugating Enzymes; D011494:Protein Kinases