ArticleComputational and structural biotechnology journal2021
Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state.
Article in Computational and structural biotechnology journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 20 citations in OpenAlex.
- Decoding C‑SH2 Domain/Peptide Interactions in SH2 Domain-Containing Tyrosine Phosphatase 2: A Molecular Framework for Rational Inhibitor Design.ACS omega · 2026Article
- Phosphatase SHP2 pathogenic mutations enhance activity by altering conformational sampling.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Phosphatase SHP2 pathogenic mutations enhance activity by altering conformational sampling.bioRxiv : the preprint server for biology · 2025Article
- The pathogenic E139D mutation stabilizes a non-canonical active state of the multi-domain phosphatase SHP2.Protein science : a publication of the Protein Society · 2025Article
- The pathogenic E139D mutation stabilizes a non-canonical active state of the multi-domain phosphatase SHP2.bioRxiv : the preprint server for biology · 2025Article
- Mechanistic Insights into the Membrane Permeabilization Activity of Antimicrobial Prenylated Isoflavonoids: A Comparative Study of Glabridin, Wighteone, and Lupiwighteone.Journal of agricultural and food chemistry · 2025Article
- Phosphopeptide binding to the N-SH2 domain of tyrosine phosphatase SHP2 correlates with the unzipping of its central β-sheet.Computational and structural biotechnology journal · 2024Article
- Targeting SHP2 Cryptic Allosteric Sites for Effective Cancer Therapy.International journal of molecular sciences · 2024Article
- Single Ion Pair Is Essential for Stabilizing SHP2's Open Conformation.Biochemistry · 2024Article
- Atomistic ensemble of active SHP2 phosphatase.Communications biology · 2023Article
- SHP2 clinical phenotype, cancer, or RASopathies, can be predicted by mutant conformational propensities.Cellular and molecular life sciences : CMLS · 2023Article
- Quantitation of autoinhibitory defects in pathogenic SHP2 mutants by differential scanning fluorimetry.Analytical biochemistry · 2023Article
- SH2 Domains: Folding, Binding and Therapeutical Approaches.International journal of molecular sciences · 2022Review
- Allosteric regulation of autoinhibition and activation of c-Abl.Computational and structural biotechnology journal · 2022Article
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Src-homology 2 domain containing phosphatase 2 (SHP2) plays a critical role in crucial signaling pathways and is involved in oncogenesis and in developmental disorders. Its structure includes two SH2 domains (N-SH2 and C-SH2), and a protein tyrosine phosphatase (PTP) domain. Under basal conditions, SHP2 is auto-inhibited, with the N-SH2 domain blocking the PTP active site. Activation involves a rearrangement of the domains that makes the catalytic site accessible, coupled to the association between the SH2 domains and cognate proteins containing phosphotyrosines. Several aspects of this transition are debated and competing mechanistic models have been proposed. A crystallographic structure of SHP2 in an active state has been reported (PDB code 6crf), but several lines of evidence suggests that it is not fully representative of the conformations populated in solution. To clarify the structural rearrangements involved in SHP2 activation, enhanced sampling simulations of the autoinhibited and active states have been performed, for wild type SHP2 and its pathogenic E76K variant. Our results demonstrate that the crystallographic conformation of the active state is unstable in solution, and multiple interdomain arrangements are populated, thus allowing association to bisphosphorylated sequences. Contrary to a recent proposal, activation is coupled to the conformational changes of the N-SH2 binding site, which is significantly more accessible in the active sate, rather than to the structure of the central β-sheet of the domain. In this coupling, a previously undescribed role for the N-SH2 BG loop emerged.
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