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Allosteric Communication across STAT3 Domains Associated with STAT3 Function and Disease-Causing Mutation.

Andrew T Namanja1, Jianghai Wang1, Ralf Buettner1

  • 1Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.

Journal of Molecular Biology
|January 18, 2016
PubMed
Summary

Signal transducer and activator of transcription 3 (STAT3) exhibits inter-domain allosteric communication. This dynamics-dependent effect, observed via NMR, impacts disease-related STAT3 functions and may occur across the STAT family.

Keywords:
HIESNMRSH2STAT3allostery

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is crucial for cellular processes.
  • Aberrant STAT3 activity is linked to cancer and hyper-immunoglobulin E syndrome (HIES).
  • STAT3 comprises distinct domains: SH2, linker (LD), DNA-binding (DBD), and coiled-coil.

Purpose of the Study:

  • To investigate inter-domain allosteric communications within STAT3.
  • To understand how mutations and ligand binding affect STAT3 structure and dynamics.
  • To explore the implications for STAT3-related diseases and other STAT proteins.

Main Methods:

  • Nuclear magnetic resonance (NMR) spectroscopy.
  • Biophysical assays to study protein-ligand interactions.
  • Analysis of disease-associated mutations (e.g., I568F in LD).

Main Results:

  • pTyr-peptide binding to the SH2 domain induces structural and dynamic changes in the LD and DBD.
  • Hydrophobic core flexibility mediates these inter-domain allosteric effects.
  • The HIES-associated I568F mutation in LD causes conformational changes across multiple STAT3 domains, reducing SH2 binding affinity.

Conclusions:

  • STAT3 exhibits dynamics-dependent inter-domain allosteric regulation.
  • Allosteric communication in STAT3 is influenced by both ligand binding and mutations.
  • These findings provide insights into STAT3 function, disease mechanisms, and potential therapeutic strategies, likely applicable to other STAT family members.