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BPV E5 Protein

Figure 1. Bovine papillomavirus E5 protein. The top shows the complete amino acid sequence of the BPV E5 protein. The bottom shows a schematic representation of the E5 dimer embedded in a cell membrane. Figure adapted from Windisch et al, Biophysical J. 99: 1764-1672 (2010).

The laboratory is interested in determining the mechanism of action of viral oncogenes, with the belief that these studies will provide new insight into signal transduction, protein-protein interactions, and the control of cell proliferation. For many years, we have studied the E5 oncoprotein of bovine papillomavirus (BPV). Only forty-four amino acids long, the BPV E5 protein is the shortest natural protein known to cause tumorigenic transformation. In transformed cells, the E5 protein exists as a dimeric transmembrane protein with a very hydrophobic central domain that spans the membranes of the Golgi apparatus and endoplasmic reticulum (Fig. 1). Thus, the E5 protein appears to be in essence a free-standing transmembrane domain, suggesting that its study will shed new light onto mechanisms of cell transformation and protein action.

Figure 2. Model for E5-mediated activation of the PDGF β receptor. Panel a shows an inactive PDGF receptor tyrosine kinase monomer, with the extracellular domain at the top. Panel b shows receptor dimer activated by PDGF (purple) binding to the extracellular domain of the PDGF receptor. Panel c shows the receptor dimer activated by the E5 dimer binding to the transmembrane domain of the receptor. Figure prepared by Yarden Opatowsky and published in DiMaio, Annu. Rev. Microbiol. 68: (2014).

We showed that the E5 protein specifically binds to the transmembrane domain of the platelet-derived growth factor ß receptor, a cellular transmembrane receptor tyrosine kinase that normally transduces signals from PDGF, a soluble ligand. The E5/PDGF receptor interaction activates the receptor in a ligand-independent fashion and results in growth stimulation and tumorigenic transformation of cells. These findings demonstrated that receptor tyrosine kinases can be activated by proteins that do not resemble their normal ligands and that a free-standing transmembrane domain is sufficient to exert specific biological activity. We used mutational analysis and isolation of compensatory mutants to show that direct interactions involving specific transmembrane and juxtamembrane amino acids in the E5 protein and the PDGF ß receptor result in dimerization and trans-phosphorylation of the receptor, and in the recruitment of cellular signaling molecules into a signal transduction complex (Fig. 2). Thus, the E5 protein acts as a specific, intramembrane crosslinker of the PDGF ß receptor. We are conducting genetic and biochemical experiments as well as molecular modeling to define the structure of this unique complex, in the belief that it will provide general new insight into the assembly of transmembrane protein complexes and signaling by receptor tyrosine kinases.

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