title: Allosteric Communication across STAT3 Domains Associated with STAT3 Function and Disease-Causing Mutation.
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.
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Namanja
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Jianghai
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Ralf
authors.initials: R
authors.lastname: Buettner
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
authors.forename: Loren
authors.initials: L
authors.lastname: Colson
authors.affiliation: Department of Molecular Medicine, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA. Electronic address: ychen@coh.org.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D006801:Humans; D009154:Mutation; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D050796:STAT3 Transcription Factor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D050796:STAT3 Transcription Factor
keywords: HIES; NMR; SH2; STAT3; allostery