Pasteurella multocida toxin activation of heterotrimeric G proteins by deamidation.
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 approximately 145 kDa protein toxin stimulates various signal transduction pathways by activating heterotrimeric G proteins of the Galpha(q), Galpha(i), and Galpha(12/13) families by using an as yet unknown mechanism. Here, we show that Pasteurella multocida toxin deamidates glutamine-205 of Galpha(i2) to glutamic acid. Therefore, the toxin inhibits the intrinsic GTPase activity of Galpha(i) and causes persistent activation of the G protein. A similar modification is also evident for Galpha(q), but not for the closely related Galpha(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.
Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 25, D-79104 Freiburg, Germany.
Joachim H C
JH
Orth
Inga
I
Preuss
Ines
I
Fester
Andreas
A
Schlosser
Brenda A
BA
Wilson
Klaus
K
Aktories
D000244:Adenosine Diphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism*; D002478:Cells, Cultured; D003641:Deamination; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D051379:Mice; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D053719:Tandem Mass Spectrometry
D001426:Bacterial Proteins; D001427:Bacterial Toxins; C062258:Pasteurella multocida toxin; D011994:Recombinant Proteins; D000244:Adenosine Diphosphate; D020962:Heterotrimeric GTP-Binding Proteins