Structural rearrangements of PDGFRβ in the membrane upon activation by the viral oncoprotein E5.

Abstract

The transmembrane protein E5 from bovine papillomavirus is the shortest naturally occurring oncoprotein. As a dimer, it activates the platelet-derived growth factor receptor β (PDGFRβ) in a ligand-independent manner by specific helix-helix interactions within the lipid bilayer. For both proteins, we determined the detailed orientations of their transmembrane helices in aligned membrane samples. Solid-state ¹⁵N-NMR was used to study either protein segment alone, as well as in the heterocomplex. Remarkably, the assembly of E5 with PDGFRβ led to structural rearrangements of both partners. Binding of E5 triggers a rotation of the PDGFRβ helices around their axes. At the same time, the E5 helices rotate in the membrane to expose Gln17 as well as Asp33, allowing their respective interaction with Thr513 and Lys499 on PDGFRβ. Based on these distinct membrane orientations, we present structural models of the heteromeric E5-PDGFRβ complex, and a mechanism for oncogenic receptor activation.