title: Mutations in the linker domain affect phospho-STAT3 function and suggest targets for interrupting STAT3 activity.
abstract: Crystallography of the cores of phosphotyrosine-activated dimers of STAT1 (132-713) and STAT3 (127-722) bound to a similar double-stranded deoxyoligonucleotide established the domain structure of the STATs and the structural basis for activation through tyrosine phosphorylation and dimerization. We reported earlier that mutants in the linker domain of STAT1 that connect the DNA-binding domain and SH2 domain can prevent transcriptional activation. Because of the pervasive importance of persistently activated STAT3 in many human cancers and the difficulty of finding useful drug candidates aimed at disrupting the pY interchange in active STAT3 dimers, we have examined effects of an array of mutants in the STAT3 linker domain. We have found several STAT3 linker domain mutants to have profound effects of inhibiting STAT3 transcriptional activation. From these results, we propose (i) there is definite functional interaction of the linker both with the DNA binding domain and with the SH2 domain, and (ii) these putative contacts provide potential new targets for small molecule-induced pSTAT3 inhibition.
authors.affiliation: Laboratory of Molecular Cell Biology, The Rockefeller University, New York, NY 10065-6399;
authors.forename: Claudia
authors.initials: C
authors.lastname: Mertens
authors.affiliation: Laboratory of Molecular Cell Biology, The Rockefeller University, New York, NY 10065-6399;
authors.forename: Bhagwattie
authors.initials: B
authors.lastname: Haripal
authors.affiliation: Laboratory of Protein and Nucleic Acid Chemistry, The Rockefeller University, New York, NY 10065-6399.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Klinge
authors.affiliation: Laboratory of Molecular Cell Biology, The Rockefeller University, New York, NY 10065-6399; darnell@rockefeller.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Darnell
mesh_terms: D019943:Amino Acid Substitution; D045744:Cell Line, Tumor; D006801:Humans; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D055503:Protein Multimerization; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D009363:Neoplasm Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: STAT3; linker domain; mutants