Structural Determinants of Phosphopeptide Binding to the N-Terminal Src Homology 2 Domain of the SHP2 Phosphatase
Open Access
- 12 May 2020
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Chemical Information and Modeling
- Vol. 60 (6), 3157-3171
- https://doi.org/10.1021/acs.jcim.0c00307
Abstract
SH2 domain-containing tyrosine phosphatase 2 (SHP2), encoded by PTPN11, plays a fundamental role in the modulation of several signaling pathways. Germline and somatic mutations in PTPN11 are associated with different rare diseases and hematologic malignancies, and recent studies have individuated SHP2 as a central node in oncogenesis and cancer drug resistance. SHP2 structure includes two Src homology 2 domains (N-SH2 and C-SH2) followed by a catalytic protein tyrosine phosphatase (PTP) domain. Under basal conditions, the N-SH2 domain blocks the active site, inhibiting phosphatase activity. Association of the N-SH2 domain with binding partners containing short amino acid motifs comprising a phosphotyrosine residue (pY) leads to N-SH2/PTP dissociation and SHP2 activation. Considering the relevance of SHP2 in signaling and disease and the central role of the N-SH2 domain in its allosteric regulation mechanism, we performed microsecond-long molecular dynamics simulations of the N-SH2 domain complexed to 12 different peptides, to define the structural and dynamical features determining the binding affinity and specificity of the domain. Phosphopeptide residues at position −2 to +5, with respect to pY, have significant interactions with the SH2 domain. In addition to the strong interaction of the pY residue with its conserved binding pocket, the complex is stabilized hydrophobically by insertion of residues +1, +3 and +5 in an apolar groove of the domain, and interaction of residue −2 with both the pY and a protein surface residue. Additional interactions are provided by hydrogen bonds formed by the backbone of residues −1, +1, +2 and +4. Finally, negatively charged residues at position +2 and +4 are involved in electrostatic interactions with two lysines (Lys89 and Lys91) specific of the SHP2 N-SH2 domain. Interestingly, the MD simulations illustrated a previously undescribed conformational flexibility of the domain, involving the core -sheet and the loop that closes the pY binding pocket.Funding Information
- Ministero dell?Istruzione, dell?Universit? e della Ricerca (PRIN 20157WW5EH_007)
- Associazione Italiana per la Ricerca sul Cancro (IG19171)
- Fondazione Umberto Veronesi
This publication has 75 references indexed in Scilit:
- Counteracting Effects Operating on Src Homology 2 Domain-containing Protein-tyrosine Phosphatase 2 (SHP2) Function Drive Selection of the Recurrent Y62D and Y63C Substitutions in Noonan Syndrome*♦Published by Elsevier BV ,2012
- Simultaneous Binding of Two Peptidyl Ligands by a Src Homology 2 DomainBiochemistry, 2011
- Structural mechanism associated with domain opening in gain‐of‐function mutations in SHP2 phosphataseProteins-Structure Function and Bioinformatics, 2011
- Canonical sampling through velocity rescalingThe Journal of Chemical Physics, 2007
- Comparison of multiple Amber force fields and development of improved protein backbone parametersProteins-Structure Function and Bioinformatics, 2006
- AMBER force-field parameters for phosphorylated amino acids in different protonation states: phosphoserine, phosphothreonine, phosphotyrosine, and phosphohistidineJournal of Molecular Modeling, 2005
- GROMACS: Fast, flexible, and freeJournal of Computational Chemistry, 2005
- SH2 domains recognize specific phosphopeptide sequencesCell, 1993
- Molecular dynamics with coupling to an external bathThe Journal of Chemical Physics, 1984
- Comparison of simple potential functions for simulating liquid waterThe Journal of Chemical Physics, 1983