The binding selectivity of the C-terminal SH3 domain of Grb2, but not its folding pathway, is dictated by its contiguous SH2 domain.

Autor:	Di Felice M; Dipartimento di Scienze Biochimiche 'A. Rossi Fanelli', Sapienza Università di Roma, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy., Pagano L; Dipartimento di Scienze Biochimiche 'A. Rossi Fanelli', Sapienza Università di Roma, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy., Pennacchietti V; Dipartimento di Scienze Biochimiche 'A. Rossi Fanelli', Sapienza Università di Roma, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy., Diop A; Dipartimento di Scienze Biochimiche 'A. Rossi Fanelli', Sapienza Università di Roma, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy., Pietrangeli P; Dipartimento di Scienze Biochimiche 'A. Rossi Fanelli', Sapienza Università di Roma, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy., Marcocci L; Dipartimento di Scienze Biochimiche 'A. Rossi Fanelli', Sapienza Università di Roma, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy., Di Matteo S; Dipartimento di Scienze Biochimiche 'A. Rossi Fanelli', Sapienza Università di Roma, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy., Malagrinò F; Dipartimento di Medicina clinica, sanità pubblica, scienze della vita e dell'ambiente, Università dell'Aquila, L'Aquila, Coppito, Italy. Electronic address: Francesca.malagrino@univaq.it., Toto A; Dipartimento di Scienze Biochimiche 'A. Rossi Fanelli', Sapienza Università di Roma, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy. Electronic address: angelo.toto@uniroma1.it., Gianni S; Dipartimento di Scienze Biochimiche 'A. Rossi Fanelli', Sapienza Università di Roma, Laboratory Affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome, Italy. Electronic address: stefano.gianni@uniroma1.it.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Apr; Vol. 300 (4), pp. 107129. Date of Electronic Publication: 2024 Mar 01.
DOI:	10.1016/j.jbc.2024.107129
Abstrakt:	The adaptor protein Grb2, or growth factor receptor-bound protein 2, possesses a pivotal role in the transmission of fundamental molecular signals in the cell. Despite lacking enzymatic activity, Grb2 functions as a dynamic assembly platform, orchestrating intracellular signals through its modular structure. This study delves into the energetic communication of Grb2 domains, focusing on the folding and binding properties of the C-SH3 domain linked to its neighboring SH2 domain. Surprisingly, while the folding and stability of C-SH3 remain robust and unaffected by SH2 presence, significant differences emerge in the binding properties when considered within the tandem context compared with isolated C-SH3. Through a double mutant cycle analysis, we highlighted a subset of residues, located at the interface with the SH2 domain and far from the binding site, finely regulating the binding of a peptide mimicking a physiological ligand of the C-SH3 domain. Our results have mechanistic implications about the mechanisms of specificity of the C-SH3 domain, indicating that the presence of the SH2 domain optimizes binding to its physiological target, and emphasizing the general importance of considering supramodular multidomain protein structures to understand the functional intricacies of protein-protein interaction domains. Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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