Oncotarget

Research Papers:

Understanding the mechanism of binding between Gab2 and the C terminal SH3 domain from Grb2

Angelo Toto, Daniela Bonetti, Alfonso De Simone and Stefano Gianni _

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Oncotarget. 2017; 8:82344-82351. https://doi.org/10.18632/oncotarget.19323

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Abstract

Angelo Toto1, Daniela Bonetti1, Alfonso De Simone2 and Stefano Gianni1

1Istituto Pasteur - Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche “A. Rossi Fanelli” and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, 00185, Rome, Italy

2Department of Life Sciences, Imperial College London, SW7 2AZ, London, UK

Correspondence to:

Stefano Gianni, email: [email protected]

Keywords: binding kinetics, folding, induced fit, intrinsically disordered proteins, mutagenesis

Received: May 10, 2017     Accepted: June 20, 2017     Published: July 18, 2017

ABSTRACT

Gab2 is a large disordered protein that regulates several cellular signalling pathways and is overexpressed in different forms of cancer. Because of its disordered nature, a detailed characterization of the mechanisms of recognition between Gab2 and its physiological partners is particularly difficult. Here we provide a detailed kinetic characterization of the binding reaction between Gab2 and the C-terminal SH3 domain of the growth factor receptor-bound protein 2 (Grb2). We demonstrate that Gab2 folds upon binding following an induced fit type mechanism, whereby recognition is characterized by the formation of an intermediate, in which Gab2 is primarily disordered. In this scenario, folding of Gab2 into the bound conformation occurs only after binding. However, an alanine scanning of the proline residues of Gab2 suggests that the intermediate contains some degree of native-like structure, which might play a role for the recognition event to take place. The results, which represent a fundamental step forward in the understanding of this functional protein-protein interaction, are discussed on the light of previous structural works on these proteins.


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