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Identification of amino acid residues in the ETS transcription factor Erg that mediate Erg-Jun/Fos-DNA ternary complex formation.

Jun, Fos, and Ets proteins belong to distinct families of transcription factors that target specific DNA elements often found jointly in gene promoters. Physical and functional interactions between these families play important roles in modulating gene expression. Previous studies have demonstrated a direct interaction between the DNA-binding domains of the two partners. However, the molecular details of the interactions have not been investigated so far. Here we used the known three-dimensional structures of the ETS DNA-binding domain and Jun/Fos heterodimer to model an ETS-Jun/Fos-DNA ternary complex. Docking procedures suggested that certain ETS domain residues in the DNA recognition helix alpha3 interact with the N-terminal basic domain of Jun. To support the model, different Erg ETS domain mutants were obtained by deletion or by single amino acid substitutions and were tested for their ability to mediate DNA binding, Erg-Jun/Fos complex formation, and transcriptional activation. We identified point mutations that affect both the DNA binding properties of Erg and its physical interaction with Jun (R367K), as well as mutations that essentially prevent transcriptional synergy with the Jun/Fos heterodimer (Y371V). These results provide a framework of the ETS/bZIP interaction linked to the manifestation of functional activity in gene regulation.

Pubmed ID: 11278640 RIS Download

Mesh terms: Amino Acid Sequence | Amino Acid Substitution | Animals | Base Sequence | Binding Sites | DNA | DNA-Binding Proteins | Dimerization | Models, Molecular | Molecular Sequence Data | Mutagenesis, Site-Directed | Nucleic Acid Conformation | Oligodeoxyribonucleotides | Oncogene Proteins | Osteosarcoma | Protein Conformation | Protein Structure, Secondary | Proto-Oncogene Proteins | Proto-Oncogene Proteins c-ets | Proto-Oncogene Proteins c-fos | Proto-Oncogene Proteins c-jun | Rats | Sequence Alignment | Sequence Deletion | Sequence Homology, Amino Acid | Trans-Activators | Transcription Factors | Transcriptional Regulator ERG | Tumor Cells, Cultured

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