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Cited by 31Cytokine Signaling Pathways and InteractionsProtein Structure and DynamicsReceptor Mechanisms and Signaling

Allosteric communication across STAT3 domains associated with STAT3 function and disease-causing mutation

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Namanja, Andrew T., Wang, Jianghai, Buettner, Ralf, Colson, Loren, Chen, Yuan·2016·Journal of Molecular Biology
DOI 10.1016/j.jmb.2016.01.003PMC PMC4767637
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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 communication observed in STAT3 likely occurs in other STATs.

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Authors
Namanja, A. T., Wang, J., Buettner, R., Colson, L., & Chen, Y.
Affiliations
City Of Hope National Medical Center (US)
Corresponding author
Chen, Yuan
ORCID
Venue
Journal of Molecular Biology
Publisher
Elsevier BV
Published
2016-02
Volume
428
Issue
3
Pages
579-589
ISSN
0022-2836 (ISSN-L)
DOI
10.1016/j.jmb.2016.01.003
PMC
PMC4767637
OpenAlex
W2238529566
Cited by
31
References
1
Citations by year
2026: 2 · 2025: 2 · 2024: 7 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 1
FWCI
1.44
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health (K01CA168958, R01GM086717, R01GM102538)
Topics
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords
STAT3, allosteric communication, inter-domain communication, SH2 domain, linker domain, DNA-binding domain, coiled-coil domain, protein dynamics, constitutive STAT3 activation, cancer
MeSH terms
Allosteric Regulation, Binding Sites, Humans, Mutation, Protein Binding, Protein Structure, Tertiary, src Homology Domains, Nuclear Magnetic Resonance, Biomolecular, STAT3 Transcription Factor, Protein Multimerization

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