Structural models of the bovine papillomavirus E5 protein

Abstract

The bovine papillomavirus E5 protein is thought to be a type II integral membrane protein that exists as a disulfide-linked homodimer in transformed cells. Polarized-infrared measurements show that the E5 dimer in membrane bilayers is largely alpha-helical and has a transmembrane orientation. Computational searches of helix-helix conformations reveal two possible low-energy dimer structures. Correlation of these results with previous mutagenesis studies on the E5 protein suggests how the E5 dimer may serve as a molecular scaffold for dimerization and ligand-independent activation of the PDGF-beta receptor. We propose that on each face of the E5 dimer a PDGF-beta receptor molecule interacts directly with Gln17 from one E5 monomer and with Asp33 from the other E5 monomer. This model accounts for the requirement of Gln17 and Asp33 for complex formation and explains genetic results that dimerization of the E5 protein is essential for cell transformation.

The bovine papillomavirus E5 protein and the PDGF β receptor: It takes two to tango

“…Additional genetic experiments utilized seven chimeric E5 constructs that forced dimerization of the E5 segments in specific orientations relative to one another, each representing one of the possible homodimer interfaces predicted by a symmetric left-handed coiled-coil configuration. Only one conformation was capable of inducing robust cell transformation and PDGFβR activation, corroborating the proposed structure of the E5 dimer (Mattoon et al, 2001; Surti et al, 1998). Taken together, these data confirm that dimerization of the E5 protein in the proper orientation is required for its ability to activate the PDGFβR.…”

“…with its hydrophilic C-terminus extending into the lumen of the endoplasmic reticulum or Golgi apparatus (Burkhardt et al, 1989). Biophysical experiments and molecular modeling indicated that the E5 protein is in fact a transmembrane dimer that adopts a symmetric left-handed coiled-coil configuration (Oates et al, 2008; Surti et al, 1998). …”

“…5). Furthermore, molecular modeling of the coiled-coil E5 dimer indicates that dimerization of the E5 protein generates two identical faces, each of which is able to bind a monomer of PDGFβR (Surti et al, 1998). On each face of the E5 dimer, one E5 monomer contributes the required glutamine to the PDGFβR binding site and the other monomer contributes the aspartic acid (Fig.…”

“…On each face of the E5 dimer, one E5 monomer contributes the required glutamine to the PDGFβR binding site and the other monomer contributes the aspartic acid (Fig. 6) (Surti et al, 1998). Thus, dimerization of the two E5 monomers generates binding sites for two PDGFβR molecules, one on each face of the E5 dimer (Fig.…”

Role of Glutamine 17 of the Bovine Papillomavirus E5 Protein in Platelet-Derived Growth Factor β Receptor Activation and Cell Transformation

“…The 44-residue E5 protein consists of a hydrophobic 30residue segment at the N terminus that spans membranes as an ␣-helix and a hydrophilic 14-residue segment at the C terminus (7,30). Extensive mutational analysis has demonstrated that four absolutely conserved residues in the E5 protein are critical for binding and activation of the PDGF ␤ receptor and for cell transformation (13,20,22,27,28).…”