ArticleProceedings of the National Academy of Sciences of the United States of America2021
The loops of the N-SH2 binding cleft do not serve as allosteric switch in SHP2 activation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 18 citations in OpenAlex.
- SHP2 as a pivotal modulator of the tumor microenvironment in gastrointestinal cancers: from mechanisms to targeted therapies.Journal of translational medicine · 2026Review
- Cancer-Causing Mutations Alter the Interplay Between Loop Dynamics and Catalysis in the Protein Tyrosine Phosphatases SHP-1 and SHP-2.bioRxiv : the preprint server for biology · 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
- Update on Structure and Function of SH2 Domains: Mechanisms and Emerging Targeting Strategies.International journal of molecular sciences · 2025Review
- 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
- 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
- Experiment-guided molecular simulations define a heterogeneous structural ensemble for theChemical science · 2023Article
- How a single mutation alters the protein structure: a simulation investigation on protein tyrosine phosphatase SHP2.RSC advances · 2023Article
- A comprehensive review of SHP2 and its role in cancer.Cellular oncology (Dordrecht, Netherlands) · 2022Review
- Discriminating between competing models for the allosteric regulation of oncogenic phosphatase SHP2 by characterizing its active state.Computational and structural biotechnology journal · 2021Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Src-homology-2 domain-containing phosphatase SHP2 is a critical regulator of signal transduction, being implicated in cell growth and differentiation. Activating mutations cause developmental disorders and act as oncogenic drivers in hematologic cancers. SHP2 is activated by phosphopeptide binding to the N-SH2 domain, triggering the release of N-SH2 from the catalytic PTP domain. Based on early crystallographic data, it has been widely accepted that opening of the binding cleft of N-SH2 serves as the key "allosteric switch" driving SHP2 activation. To test the putative coupling between binding cleft opening and SHP2 activation as assumed by the allosteric switch model, we critically reviewed structural data of SHP2, and we used extensive molecular dynamics (MD) simulation and free energy calculations of isolated N-SH2 in solution, SHP2 in solution, and SHP2 in a crystal environment. Our results demonstrate that the binding cleft in N-SH2 is constitutively flexible and open in solution and that a closed cleft found in certain structures is a consequence of crystal contacts. The degree of opening of the binding cleft has only a negligible effect on the free energy of SHP2 activation. Instead, SHP2 activation is greatly favored by the opening of the central β-sheet of N-SH2. We conclude that opening of the N-SH2 binding cleft is not the key allosteric switch triggering SHP2 activation.
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