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PNAS 106 (17): 7179-7184

Copyright © 2009 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / MICROBIOLOGY

Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation

Joachim H. C. Ortha,1, Inga Preussa,b,1, Ines Festera, Andreas Schlosserc, Brenda A. Wilsond, and Klaus Aktoriesa,2

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 Pasteurella multocida, which causes pasteurellosis in men and animals and atrophic rhinitis in rabbits and pigs. The {approx}145 kDa protein toxin stimulates various signal transduction pathways by activating heterotrimeric G proteins of the G{alpha}q, G{alpha}i, and G{alpha}12/13 families by using an as yet unknown mechanism. Here, we show that Pasteurella multocida toxin deamidates glutamine-205 of G{alpha}i2 to glutamic acid. Therefore, the toxin inhibits the intrinsic GTPase activity of G{alpha}i and causes persistent activation of the G protein. A similar modification is also evident for G{alpha}q, but not for the closely related G{alpha}11, which is not a substrate of Pasteurella multocida toxin. Our data identify the {alpha}-subunits of heterotrimeric G proteins as the direct molecular target of Pasteurella multocida toxin and indicate that the toxin does not act like a protease, which was suggested from its thiol protease-like catalytic triad, but instead causes constitutive activation of G proteins by deamidase 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.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

This article contains supporting information online at www.pnas.org/cgi/content/full/0900160106/DCSupplemental.

2To whom correspondence should be addressed. E-mail: klaus.aktories{at}pharmakol.uni-freiburg.de


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