Demonstration of Binding Induced Structural Plasticity in a SH2 Domain
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...
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Frontiers Media S.A.
2020-05-01
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| Series: | Frontiers in Molecular Biosciences |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmolb.2020.00089/full |
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| author | Lorenzo Visconti Angelo Toto James A. Jarvis Francesca Troilo Francesca Malagrinò Alfonso De Simone Stefano Gianni |
| author_facet | Lorenzo Visconti Angelo Toto James A. Jarvis Francesca Troilo Francesca Malagrinò Alfonso De Simone Stefano Gianni |
| author_sort | Lorenzo Visconti |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T14:33:26Z |
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| id | doaj.art-5a4ca9ab384b47d3b4a7921b00dbfbb7 |
| institution | Directory Open Access Journal |
| issn | 2296-889X |
| language | English |
| last_indexed | 2024-12-10T14:33:26Z |
| publishDate | 2020-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Molecular Biosciences |
| spelling | doaj.art-5a4ca9ab384b47d3b4a7921b00dbfbb72022-12-22T01:44:53ZengFrontiers Media S.A.Frontiers in Molecular Biosciences2296-889X2020-05-01710.3389/fmolb.2020.00089543314Demonstration of Binding Induced Structural Plasticity in a SH2 DomainLorenzo Visconti0Angelo Toto1James A. Jarvis2Francesca Troilo3Francesca Malagrinò4Alfonso De Simone5Stefano Gianni6Istituto Pasteur – Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche “A. Rossi Fanelli” and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, Rome, ItalyIstituto Pasteur – Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche “A. Rossi Fanelli” and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, Rome, ItalyDepartment of Life Sciences, Imperial College London, London, United KingdomIstituto Pasteur – Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche “A. Rossi Fanelli” and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, Rome, ItalyIstituto Pasteur – Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche “A. Rossi Fanelli” and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, Rome, ItalyDepartment of Life Sciences, Imperial College London, London, United KingdomIstituto Pasteur – Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche “A. Rossi Fanelli” and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, Rome, ItalySH2 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.https://www.frontiersin.org/article/10.3389/fmolb.2020.00089/fullallosteric networkskineticsmutagenesispeptide bindingNMR |
| spellingShingle | Lorenzo Visconti Angelo Toto James A. Jarvis Francesca Troilo Francesca Malagrinò Alfonso De Simone Stefano Gianni Demonstration of Binding Induced Structural Plasticity in a SH2 Domain Frontiers in Molecular Biosciences allosteric network skinetics mutagenesis peptide binding NMR |
| title | Demonstration of Binding Induced Structural Plasticity in a SH2 Domain |
| title_full | Demonstration of Binding Induced Structural Plasticity in a SH2 Domain |
| title_fullStr | Demonstration of Binding Induced Structural Plasticity in a SH2 Domain |
| title_full_unstemmed | Demonstration of Binding Induced Structural Plasticity in a SH2 Domain |
| title_short | Demonstration of Binding Induced Structural Plasticity in a SH2 Domain |
| title_sort | demonstration of binding induced structural plasticity in a sh2 domain |
| topic | allosteric network skinetics mutagenesis peptide binding NMR |
| url | https://www.frontiersin.org/article/10.3389/fmolb.2020.00089/full |
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