Pasteurella multocida produces a 146-kDa protein toxin (PMT), which activates multiple cellular signal transduction pathways, resulting in the activation of phospholipase C, RhoA, Jun kinase, and extracellular signal-regulated kinase. Using G␣ q /G␣ 11 -deficient cells, it was shown that the PMT-induced pleiotropic effects are mediated by G␣ q but not by the highly related G␣ 11 protein (Zywietz, A., Gohla, A., Schmelz, M., Schultz, G., and Offermanns, S. (2001) J. Biol. Chem. 276, 3840 -3845). Here we studied the molecular basis of the unique specificity of PMT to distinguish between G␣ q and/or G␣ 11 . Infection of G␣ q/11 -deficient cells with retrovirus-encoding G␣ q caused reconstitution of PMT-induced activation of phospholipase C, whereas G␣ 11 -encoding virus did not reconstitute PMT activity. Chimeras between G␣ q and/or G␣ 11 revealed that a peptide region of G␣ q , covering amino acid residues 105-113, is essential for the action of PMT to activate phospholipase C. Exchange of glutamine 105 or asparagine 109 of G␣ 11 , which are located in the all-helical domain of the G␣ subunit, with the equally positioned histidines of G␣ q , renders G␣ 11 capable of transmission PMT-induced phospholipase C activation. The data indicate that the all-helical domain of G␣ q is essential for the action of PMT and suggest an essential functional role of this domain in signal transduction via G q proteins.The Pasteurella multocida is a facultative pathogen, which cause bite wound infections, pneumonia, endocarditis, and septicemia in men. In pigs, the pathogen induces atrophic rhinitis, which is characterized by a loss of nasal turbinate bone (1, 2). The 146-kDa protein toxin P. multocida toxin (PMT) 1 is the major virulence factor of the pathogen, the causative agent of atrophic rhinitis, and is responsible for the osteolytic activity of bacteria (1,(3)(4)(5). PMT consists of 1285 amino acid residues. It is generally accepted that the toxin is structured according to a typical AB toxin. Initial studies revealed that the N terminus of PMT is involved in the binding and in translocation of the toxin into target cells (6), whereas the biologically active domain is located in the C-terminal part of the protein (6, 7). This concept is in line with a significant sequence similarity of PMT at its N terminus with the N-terminal part of the cytotoxic necrotizing factor of Escherichia coli that is also involved in binding and translocation. According to the hypothesis that the C terminus of PMT carries the biological activity, an essential cysteine residue (Cys 1165 ) was identified at the C terminus (8). The change of Cys 1165 to serine blocked toxin activity but not cell binding. In addition, histidine residues (His 1205 and His 1223 ) in this part of the toxin were recognized to be essential for the activity of PMT (9).PMT activates numerous cellular signal transduction pathways. It is a strong mitogen and stimulates DNA synthesis and proliferation in several cell lines (10 -14). The mitogenic actions of PMT appear to d...
