Phosphotyrosine couples peptide binding and SHP2 activation via a dynamic allosteric network.
Cast your vote
You can rate an item by clicking the amount of stars they wish to award to this item.
When enough users have cast their vote on this item, the average rating will also be shown.
Your vote was cast
Thank you for your feedback
Thank you for your feedback
MetadataShow full item record
AbstractSHP2 is a ubiquitous protein tyrosine phosphatase, whose activity is regulated by phosphotyrosine (pY)-containing peptides generated in response to extracellular stimuli. Its crystal structure reveals a closed, auto-inhibited conformation in which the N-terminal Src homology 2 (N-SH2) domain occludes the catalytic site of the phosphatase (PTP) domain. High-affinity mono-phosphorylated peptides promote catalytic activity by binding to N-SH2 and disrupting the interaction with the PTP. The mechanism behind this process is not entirely clear, especially because N-SH2 is incapable of accommodating complete peptide binding when SHP2 is in the auto-inhibited state. Here, we show that pY performs an essential role in this process; in addition to its contribution to overall peptide-binding energy, pY-recognition leads to enhanced dynamics of the N-SH2 EF and BG loops via an allosteric communication network, which destabilizes the N-SH2–PTP interaction surface and simultaneously generates a fully accessible binding pocket for the C-terminal half of the phosphopeptide. Subsequently, full binding of the phosphopeptide is associated with the stabilization of activated SHP2. We demonstrate that this allosteric network exists only in N-SH2, which is directly involved in the regulation of SHP2 activity, while the C-terminal SH2 domain (C-SH2) functions primarily to recruit high-affinity bidentate phosphopeptides.
CitationComput Struct Biotechnol J. 2021 Apr 20;19:2398-2415. doi: 10.1016/j.csbj.2021.04.040.
AffiliationHZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.
The following license files are associated with this item:
- Creative Commons
- Structural Determinants of Phosphopeptide Binding to the N-Terminal Src Homology 2 Domain of the SHP2 Phosphatase.
- Authors: Anselmi M, Calligari P, Hub JS, Tartaglia M, Bocchinfuso G, Stella L
- Issue date: 2020 Jun 22
- Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state.
- Authors: Calligari P, Santucci V, Stella L, Bocchinfuso G
- Issue date: 2021
- The loops of the N-SH2 binding cleft do not serve as allosteric switch in SHP2 activation.
- Authors: Anselmi M, Hub JS
- Issue date: 2021 Apr 27
- Exploring the Allosteric Mechanism of Src Homology-2 Domain-Containing Protein Tyrosine Phosphatase 2 (SHP2) by Molecular Dynamics Simulations.
- Authors: Wang Q, Zhao WC, Fu XQ, Zheng QC
- Issue date: 2020