Linear motif combination and conservation of flexibility determines the displacement ability of an intrinsically disordered viral oncoprotein

GONZALEZ FOUTEL N; SANCHEZ, IE; DE PRAT GAY, GONZALO; GLAVINA JULIANA; CHEMES LUCÍA BEATRIZ

Belgrado

Conferencia; 2nd NGP-NET Symposium on Non Globular Proteins; 2016

COST Action on Non Globular Proteins

In the present work, we have explored the biophysical basis for efficient disruption of host protein-protein interactions by a viral oncoprotein. We studied the interaction between the intrinsically disordered E1A protein from human adenovirus and the retinoblastoma (Rb) cellular tumor suppressor. This interaction is mediated by two highly conserved linear motifs present within E1A, which are joined by a 70-residue linker region. Each of these motifs binds to a distinct and highly conserved surface on the RbAB domain. The E1A region harboring both motifs was found to bind with 1:1 stoichiometry and extremely high (KD = 24 pM) affinity to Rb. Even when the individual viral motifs establish lower affinity interactions (KD = 140 nM) compared to the cellular E2F counterpart (KD = 12 nM) the arrangement of two motifs joined by a disordered linker explains the effectiveness of the E1A protein, where one motif (LxCxE) acts as a docking site, increasing the effective concentration of the motif that competitively displaces E2F. A simple model derived from polymer physics predicts the compound affinity with excellent accuracy, indicating that the linker region joining both E1A motifs behaves as a flexible polymer of optimal length. Sequence conservation and affinity prediction analyses reveal that disordered nature and optimal length are highly conserved within the E1A protein family. These evidences suggest that the effectiveness of viral proteins in disrupting the cellular network relies on both the presence of distinct motif combinations as well as on conservation of flexibility within specific viral protein regions.