Inactivation of Ras by Clostridium sordellii lethal toxin-catalyzed glucosylation.
The lethal toxin (LT) from Clostridium sordellii belongs to the family of large clostridial cytotoxins causing morphological alterations in cultured cell lines accompanied by destruction of the actin cytoskeleton. C. sordellii LT exhibits 90% homology to Clostridium difficile toxin B, which has been recently identified as a monoglucosyltransferase (Just, I., Selzer, J., Wilm, M., von Eichel-Streiber, C., Mann, M., and Aktories, K. (1995) Nature 375, 500-503). We report here that LT too is a glucosyltransferase, which uses UDP-glucose as cosubstrate to modify low molecular mass GTPases. LT selectively modifies Rac and Ras, whereas the substrate specificity of toxin B is confined to the Rho subfamily proteins Rho, Rac, and Cdc42, which participate in the regulation of the actin cytoskeleton. In Rac, both toxin B and LT share the same acceptor amino acid, threonine 35. Glucosylation of Ras by LT results in inhibition of the epidermal growth factor-stimulated p42/p44 MAP-kinase signal pathway. LT is the first bacterial toxin to inactivate Ras in intact cells.
Just
I
I
Institut für Pharmakologie und Toxikologie der Universität Freiburg, Hermann-Herder-Strasse 5, D-79104 Freiburg, Germany.
Selzer
J
J
Hofmann
F
F
Green
G A
GA
Aktories
K
K
D016475:3T3 Cells; D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002413:Cations, Divalent; D003013:Clostridium / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D005964:Glucosyltransferases / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D051379:Mice; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D051381:Rats; D020744:rac GTP-Binding Proteins
D001427:Bacterial Toxins; D002413:Cations, Divalent; C072292:lethal toxin LT, Clostridium sordellii; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D005964:Glucosyltransferases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D016283:Proto-Oncogene Proteins p21(ras); D020744:rac GTP-Binding Proteins