Demonstration of binding induced structural plasticity in a SH2 domain
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
SH2 domains are common protein interaction domains able to recognize short aminoacidic sequences presenting a phosphorylated tyrosine (pY). In spite of their fundamental importance for cell physiology there is a lack of information about the mechanism by which these domains recognize and bind their natural ligands. The N-terminal SH2 (N-SH2) domain of PI3K mediates the interaction with different scaffolding proteins and is known to recognize a specific pY-X-X-M consensus sequence. These interactions are at the cross roads of different molecular pathways and play a key role for cell development and division. By combining mutagenesis, chemical kinetics and NMR, here we provide a complete characterization of the interaction between N-SH2 and a peptide mimicking the scaffolding protein Gab2. Our results highlight that N-SH2 is characterized by a remarkable structural plasticity, with the binding reaction being mediated by a diffused structural region and not solely by the residues located in the binding pocket. Furthermore, the analysis of kinetic data allow us to pinpoint an allosteric network involving residues far from the binding pocket involved in specificity. Results are discussed on the light of previous works on the binding properties of SH2 domains.
Date Issued
2020-05-12
Date Acceptance
2020-04-17
Citation
Frontiers in Molecular Biosciences, 2020, 7
ISSN
2296-889X
Publisher
Frontiers Media
Journal / Book Title
Frontiers in Molecular Biosciences
Volume
7
Copyright Statement
© 2020 Visconti, Toto, Jarvis, Troilo, Malagrinò, De Simone and Gianni. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Sponsor
Medical Research Council (MRC)
Grant Number
MR/R000255/1
Publication Status
Published
Article Number
ARTN 89