Understanding the mechanism of recognition between Gab2 and its physiological partners
GAB2 is a scaffolding protein that, in the embryonic and postnatal development, is involved in various cellular processes, including cell proliferation, survival, migration, and differentiation. GAB2 is implicated in several cancers of both solid and haematological origin; being overexpressed in breast, gastric, lung and haematological cancers. This project is based on the hypothesis that an effective chemotherapeutic strategy would be that of interfering with the GAB2 protein-protein interaction network.
The structural architecture of GAB2 consists of an N-terminal PH domain (about 120 aa), while the reminder of the protein is essentially disordered (total length 676 amino acids). Despite this large portion of GAB2 is disordered, it is nevertheless functional and extremely important, as it mediates directly the interaction with the many cytoplasmic partners, containing SH2 or SH3 domains, and folds upon binding. Because of its highly dynamic properties, the structure of GAB2 has, to date, escaped an experimental characterization. The experimental plan is therefore to characterize by fluorescence monitored equilibrium and kinetics the interactions between GAB2 and its physiological partners and to pinpoint, by site-directed mutagenesis, the critical residues in the function of GAB2.