The bovine papillomavirus E5 protein and the PDGF beta receptor: it takes two to tango.
The extremely hydrophobic, 44-amino acid bovine papillomavirus (BPV) E5 protein is the smallest known oncoprotein, which orchestrates cell transformation by causing ligand-independent activation of a cellular receptor tyrosine kinase, the platelet-derived growth factor beta receptor (PDGFbetaR). The E5 protein forms a dimer in transformed cells and is essentially an isolated membrane-spanning segment that binds directly to the transmembrane domain of the PDGFbetaR, inducing receptor dimerization, autophosphorylation, and sustained mitogenic signaling. There are few sequence constraints for activity as long as the overall hydrophobicity of the E5 protein and its ability to dimerize are preserved. Nevertheless, the E5 protein is highly specific for the PDGFbetaR and does not activate other cellular proteins. Genetic screens of thousands of small, artificial hydrophobic proteins with randomized transmembrane domains inserted into an E5 scaffold identified proteins with diverse transmembrane sequences that activate the PDGFbetaR, including some activators as small as 32-amino acids. Analysis of these novel proteins has provided new insight into the requirements for PDGFbetaR activation and specific transmembrane recognition in general. These results suggest that small, transmembrane proteins can be constructed and selected that specifically bind to other cellular or viral transmembrane target proteins. By using this approach, we have isolated a 44-amino acid artificial transmembrane protein that appears to activate the human erythropoietin receptor. Studies of the tiny, hydrophobic BPV E5 protein have not only revealed a novel mechanism of viral oncogenesis, but have also suggested that it may be possible to develop artificial small proteins that specifically modulate much larger target proteins by acting within cellular or viral membranes.
Talbert-Slagle
Kristina
K
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06510, USA.
DiMaio
Daniel
D
D000595:Amino Acid Sequence; D052688:Bovine papillomavirus 1 / Q000378:metabolism*; D002472:Cell Transformation, Viral; D008565:Membrane Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009856:Oncogene Proteins, Viral / Q000378:metabolism*; D011485:Protein Binding; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*
D008565:Membrane Proteins; D009856:Oncogene Proteins, Viral; C054304:oncogene protein E5, Bovine papillomavirus type 1; D020797:Receptor, Platelet-Derived Growth Factor beta