VIRAL PROTEINS CONTROL THE RETINOBLASTOMA REGULATORY NETWORK BY MIMICKING PROTEIN-PROTEIN INTERACTION MODULES

CHEMES, L.B.; DE PRAT-GAY, G.

La Reserva Cardales, Campana, Buenos Aires Argentina

Conferencia; Exciting Biologies Series: Biology in Balance; 2009

Cell Press, Massachusets General Hospital and IPSEN Foundation

Many viruses ensure viral genome replication through control of the cell replication machinery. In order to achieve this goal, the viral proteins must efficiently interfere with the cellular protein-protein interaction networks that mediate control of DNA replication and cell division. These networks are complex, formed by a large number of interactions, and highly robust to mutation of most individual proteins. However, perturbation of some highly connected “hub” proteins severely alters network function. A wide diversity of viral proteins target these hub proteins in the host. The retinoblastoma (Rb) protein is a hub protein in the cell cycle network and is targeted by proteins from many oncogenic and teratogenic viruses. We have explored the interaction between the human papillomavirus E7 protein and Rb by quantifying the affinity of all E7 domains for Rb, both in isolation and in the context of the full-length protein. We found that the E7-Rb interaction involves multiple interaction surfaces and can be regulated by phosphorylation. The Rb interaction modules of E7 are present throughout viral and cellular Rb targets with a wide range of affinities and in proteins with radically different functions and folding topologies. These modules are structurally diverse, including both linear motifs and folded domains. We conclude that viral proteins achieve a subtle perturbation of the different interactions and surfaces that integrate the Rb network by using many different interaction modules that mimic selected pieces of the cellular machinery.