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

Journal of Molecular Biology
Andrew T NamanjaYuan Chen

Abstract

STAT3 is a member of STAT (signal transducer and activator of transcription) transcription activators. Aberration in STAT3 activity due to constitutive activation or mutations leads to diseases such as cancer and hyper-immunoglobulin E syndrome (HIES). STAT3 contains several structured domains including the Src homology 2 domain (SH2), linker domain (LD), DNA-binding domain (DBD) and the coiled-coil domain. Here we report the discovery of inter-domain allosteric communications in STAT3 from studies using nuclear magnetic resonance (NMR) and other methods. We found that pTyr-peptide interactions with SH2 cause structural and dynamics changes in LD and DBD. The inter-domain allosteric effect is likely mediated by the flexibility in the hydrophobic core. In addition, a mutation in LD found in HIES (I568F) induces NMR chemical shift perturbation in SH2, DBD and the coiled-coil domain, suggesting conformational changes in these domains. Consistent with conformational changes in SH2, the I568F mutant reduces SH2's binding affinity to a pTyr-containing peptide. This study provides an example of dynamics-dependent allosteric effects, and due to the structural conservation of the STAT family of proteins, the inter-domain allosteric comm...Continue Reading

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Citations

Sep 11, 2019·Chemistry : a European Journal·Kalaiselvi NatarajanThorsten Berg
Apr 1, 2020·Chembiochem : a European Journal of Chemical Biology·Julian Gräb, Thorsten Berg
Jul 14, 2020·Chemical Biology & Drug Design·Nigus D Ambaye, Hua E Yu
Aug 24, 2018·Frontiers in Pharmacology·Song WuHaiyang Yu
May 12, 2018·International Journal of Oncology·Yin ShiXia Li

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