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Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation
Joachim H. C. Ortha,1,
Brenda A. Wilsond, and
aInstitut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, D-79104 Freiburg, Germany; bFaculty of Biology, Albert-Ludwigs-Universität Freiburg, Schaenzlestrasse 1, 79104 Freiburg, Germany; cZentrum für Biosystemanalyse, Albert-Ludwigs-Universität Freiburg, Habsburgerstrasse 49, 79104 Freiburg, Germany; and dDepartment of Microbiology, University of Illinois at Urbana-Champaign, 601 South Goodwin, Urbana, IL 61801
Edited by R. John Collier, Harvard Medical School, Boston, MA, and approved March 11, 2009
Received for publication January 7, 2009.
Abstract:Pasteurella multocida toxin is a major virulence factor of Pasteurellamultocida, which causes pasteurellosis in men and animals andatrophic rhinitis in rabbits and pigs. The 145 kDa protein toxinstimulates various signal transduction pathways by activatingheterotrimeric G proteins of the Gq, Gi, and G12/13 familiesby using an as yet unknown mechanism. Here, we show that Pasteurellamultocida toxin deamidates glutamine-205 of Gi2 to glutamicacid. Therefore, the toxin inhibits the intrinsic GTPase activityof Gi and causes persistent activation of the G protein. A similarmodification is also evident for Gq, but not for the closelyrelated G11, which is not a substrate of Pasteurella multocidatoxin. Our data identify the -subunits of heterotrimeric G proteinsas the direct molecular target of Pasteurella multocida toxinand indicate that the toxin does not act like a protease, whichwas suggested from its thiol protease-like catalytic triad,but instead causes constitutive activation of G proteins bydeamidase activity.
Key Words: bacterial protein toxin Gi protein posttranslational modification transglutaminase
Author contributions: J.H.C.O. and K.A. designed research; J.H.C.O.,I.P., I.F., A.S., and B.A.W. performed research; J.H.C.O., I.P.,I.F., and K.A. analyzed data; and J.H.C.O., B.A.W., and K.A.wrote the paper.
1J.H.C.O. and I.P. contributed equally to this work.
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