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Protein Kinases and Phosphatases02:54

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Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
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Phosphatase SHP2 pathogenic mutations enhance activity by altering conformational sampling.

Andrew W Glaser1, Ricardo A P Pádua1,2, Adedolapo M Ojoawo1,2

  • 1Department of Biochemistry and Biophysics, Brandeis University and HHMI, Waltham, MA 02453.

Proceedings of the National Academy of Sciences of the United States of America
|January 13, 2026
PubMed
Summary
This summary is machine-generated.

The T42A mutation in SHP2 protein tyrosine phosphatase (SHP2) enhances phosphopeptide binding by stabilizing a zipped conformation. This study reveals atomic mechanisms of SHP2 regulation and dysregulation for cellular signaling.

Keywords:
NMRSH2SHP2allosterydynamics

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Area of Science:

  • Molecular Biology
  • Structural Biology
  • Biochemistry

Background:

  • SH2 domains mediate cellular signaling by binding phosphopeptide ligands.
  • SHP2 is a key regulator of cellular signaling, and its dysregulation is implicated in disease.
  • The precise mechanisms of SH2 domain binding and SHP2 activation are not fully understood.

Purpose of the Study:

  • To investigate the atomic mechanisms of SHP2 regulation and dysregulation.
  • To elucidate the controversial mechanisms of E139D and T42A mutations in SHP2.
  • To resolve the paradox of T42A mutation increasing binding affinity despite disrupting a key hydrogen bond.

Main Methods:

  • X-ray ensemble refinement
  • NMR relaxation studies
  • Computational modeling

Main Results:

  • The T42A mutation shifts the N-SH2 domain toward a stabilized zipped β-sheet conformation.
  • This conformational shift suppresses millisecond conformational exchange, enhancing phosphopeptide binding affinity.
  • The findings provide a structural basis for T42A-induced hyperactivation and reconcile conflicting models of SHP2 activation.

Conclusions:

  • Complementary structural and dynamic approaches reveal SHP2 regulatory mechanisms.
  • The study provides insights into SH2-mediated phosphopeptide recognition.
  • Understanding these mechanisms can inform therapeutic strategies for SHP2-related diseases.