Decoding SHP2 mutations by computational saturation mutagenesis

Area of Science:

• Biochemistry
• Molecular Biology
• Genetics

Background:

• Src-homology-2-containing protein tyrosine phosphatase 2 (SHP2) regulates crucial cellular processes.
• SHP2 normally exists in a self-inhibited state, preventing aberrant activation.
• Mutations disrupting this autoinhibition are linked to developmental disorders and cancer.

Purpose of the Study:

• To systematically analyze the functional impact of SHP2 single-amino acid substitutions.
• To identify key residues and structural changes associated with SHP2 pathogenicity.
• To develop a predictive framework for uncharacterized SHP2 variants.

Main Methods:

• Computational saturation mutagenesis of SHP2 SH2 and PTP domains (>9000 substitutions).
• Analysis of binding energy changes to predict conformational stability.
• Functional assays to assess enzymatic activity, signaling, and proliferation.
• Integration of clinical data to correlate variants with disease.

Main Results:

• Identified key residues (e.g., A72, G503) destabilizing the autoinhibited conformation.
• Demonstrated that SH2 and PTP domain mutations enhance SHP2 activity, signaling, and proliferation.
• Pathogenic variants were found to preferentially adopt destabilizing conformations.

Conclusions:

• Conformational opening is a primary driver of SHP2 pathogenicity.
• Structural destabilization directly links SHP2 mutations to disease.
• Provides a comprehensive map and predictive framework for SHP2 variant interpretation.