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 oncoprotein stimulates signal transduction through activation of the platelet-derived growth factor (PDGF) receptor, and E5 exhibits limited amino acid sequence similarity with PDGF. Results presented here suggest that a key feature of the hydrophobic transmembrane domain is an amino acid side chain that participates in interhelical hydrogen bond formation. These data are reminiscent of the activated neu oncogene, in which a point mutation in the transmembrane domain leads to ligand-independent dimerization and activation of a receptor tyrosine kinase. Significantly, the transmembrane domain of E5 can be largely replaced by the transmembrane domain from the activated neu receptor tyrosine kinase. Extensive mutagenesis defines the minimal structural features required 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 that E5 and PDGF activate the PDGF receptor by distinct mechanisms.
Meyer
A N
AN
Department of Chemistry/Division of Biochemistry, University of California at San Diego, La Jolla 92093-0322.
Xu
Y F
YF
Webster
M K
MK
Smith
A E
AE
Donoghue
D J
DJ
D000595:Amino Acid Sequence; D001483:Base Sequence; D052688:Bovine papillomavirus 1 / Q000378:metabolism*; D002472:Cell Transformation, Viral; D004279:DNA, Viral; D004220:Disulfides; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009856:Oncogene Proteins, Viral / Q000737:chemistry* / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011487:Protein Conformation; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism
D004279:DNA, Viral; D004220:Disulfides; D009856:Oncogene Proteins, Viral; D010982:Platelet-Derived Growth Factor; C054304:oncogene protein E5, Bovine papillomavirus type 1; D017479:Receptors, Platelet-Derived Growth Factor