CELLULAR-TRANSFORMATION BY A TRANSMEMBRANE PEPTIDE - STRUCTURAL REQUIREMENTS FOR THE BOVINE PAPILLOMAVIRUS E5 ONCOPROTEIN

The E5 oncoprotein of bovine papillomavirus, only 44 amino acids long, occurs as a disulfide-bonded transmembrane dimer. This remarkable onc oprotein stimulates signal transduction through activation of the plat elet-derived growth factor (PDGF) receptor, and E5 exhibits limited am ino acid sequence similarity with PDGF. Results presented here suggest that a key feature of the hydrophobic transmembrane domain is an amin o acid side chain that participates in interhelical hydrogen bond form ation. These data are reminiscent of the activated neu oncogene, in wh ich a point mutation in the transmembrane domain leads to ligand-indep endent dimerization and activation of a receptor tyrosine kinase. Sign ificantly, the transmembrane domain of E5 can be largely replaced by t he transmembrane domain from the activated neu receptor tyrosine kinas e. Extensive mutagenesis defines the minimal structural features requi red for transformation by the E5 oncoprotein as, first, the ability to dimerize and, second, presentation of a negatively charged residue at the extracellular side of the membrane. The biological activity of E5 mutants that lack most amino acid residues similar to PDGF suggests t hat E5 and PDGF activate the PDGF receptor by distinct mechanisms.