ArticleInternational journal of molecular sciences2020
Unveiling the Molecular Basis of the Noonan Syndrome-Causing Mutation T42A of SHP2.
Article in International journal of molecular sciences, 2020. 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, 22 citations in OpenAlex.
- Multiplexed single-cell transcriptomics reveals diverse phenotypic outcomes for pathogenic SHP2 variants.Science advances · 2026Article
- Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants.EMBO reports · 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
- Proximity-labeling proteomics reveals remodeled interactomes and altered localization of pathogenic SHP2 variants.bioRxiv : the preprint server for biology · 2025Article
- The pathogenic T42A mutation in SHP2 rewires the interaction specificity of its N-terminal regulatory domain.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The pathogenic T42A mutation in SHP2 rewires the interaction specificity of its N-terminal regulatory domain.bioRxiv : the preprint server for biology · 2024Article
- SH2 Domains: Folding, Binding and Therapeutical Approaches.International journal of molecular sciences · 2022Review
- Characterization of early and late transition states of the folding pathway of a SH2 domain.Protein science : a publication of the Protein Society · 2022Article
- Modeling (not so) rare developmental disorders associated with mutations in the protein-tyrosine phosphatase SHP2.Frontiers in cell and developmental biology · 2022Review
- Determining folding and binding properties of the C-terminal SH2 domain of SHP2.Protein science : a publication of the Protein Society · 2021Article
- Understanding the Mechanism of Recognition of Gab2 by the N-SH2 Domain of SHP2.Life (Basel, Switzerland) · 2020Article
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Authors and funding
5 authors at 2 institutions in 1 country.
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Abstract
Noonan syndrome (NS) is a genetic disorder caused by the hyperactivation of the RAS-MAPK molecular pathway. About 50% of NS cases are caused by mutations affecting the SHP2 protein, a multi-domain phosphatase with a fundamental role in the regulation of the RAS-MAPK pathway. Most NS-causing mutations influence the stability of the inactive form of SHP2. However, one NS-causing mutation, namely T42A, occurs in the binding pocket of the N-SH2 domain of the protein. Here, we present a quantitative characterization of the effect of the T42A mutation on the binding of the N-terminal SH2 domain of SHP2 with a peptide mimicking Gab2, a fundamental interaction that triggers the activation of the phosphatase in the cellular environment. Our results show that whilst the T42A mutation does not affect the association rate constant with the ligand, it causes a dramatic increase of the affinity for Gab2. This effect is due to a remarkable decrease of the microscopic dissociation rate constant of over two orders of magnitudes. In an effort to investigate the molecular basis of the T42A mutation in causing Noonan syndrome, we also compare the experimental results with a more conservative variant, T42S. Our findings are discussed in the context of the structural data available on SHP2.
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