Structural and functional characterization of an atypical activation domain in erythroid Krüppel-like factor (EKLF)
Copyright policy )Structural and functional characterization of an atypical activation domain in erythroid Krüppel-like factor (EKLF)
Erythroid Krüppel-like factor (EKLF) plays an important role in erythroid development by stimulating β-globin gene expression. We have examined the details by which the minimal transactivation domain (TAD) of EKLF (EKLFTAD) interacts with several transcriptional regulatory factors. We report that EKLFTAD displays homology to the p53TAD and, like the p53TAD, can be divided into two functional subdomains (EKLFTAD1 and EKLFTAD2). Based on sequence analysis, we found that EKLFTAD2 is conserved in KLF2, KLF4, KLF5, and KLF15. In addition, we demonstrate that EKLFTAD2 binds the amino-terminal PH domain of the Tfb1/p62 subunit of TFIIH (Tfb1PH/p62PH) and four domains of CREB-binding protein/p300. The solution structure of the EKLFTAD2/Tfb1PH complex indicates that EKLFTAD2 binds Tfb1PH in an extended conformation, which is in contrast to the α-helical conformation seen for p53TAD2 in complex with Tfb1PH. These studies provide detailed mechanistic information into EKLFTAD functions as well as insights into potential interactions of the TADs of other KLF proteins. In addition, they suggest that not only have acidic TADs evolved so that they bind using different conformations on a common target, but that transitioning from a disordered to a more ordered state is not a requirement for their ability to bind multiple partners.
- University of Montreal Canada
- Icahn School of Medicine at Mount Sinai United States
- University of Queensland Australia
- University of Queensland Australia
Models, Molecular, Beta-globin locus, CREB-binding-protein, Protein Conformation, Molecular Sequence Data, Kruppel-Like Transcription Factors, Tfb1 subunit, Calorimetry, Gene, Transcription factor IIE, Kruppel-Like Factor 4, NMR spectroscopy, Humans, Amino Acid Sequence, Cloning, Molecular, Nuclear Magnetic Resonance, Biomolecular, Intrinsically unstructured domain, P53, Binding Sites, Transactivation domain, TFIIH, Sequence Homology, Amino Acid, Hematopoiesis, Terminal domain, Mutagenesis, Site-Directed, NMR structure, Transcriptional activators, Transcription factor, K562 Cells, Protein Binding, Transcription Factors
Models, Molecular, Beta-globin locus, CREB-binding-protein, Protein Conformation, Molecular Sequence Data, Kruppel-Like Transcription Factors, Tfb1 subunit, Calorimetry, Gene, Transcription factor IIE, Kruppel-Like Factor 4, NMR spectroscopy, Humans, Amino Acid Sequence, Cloning, Molecular, Nuclear Magnetic Resonance, Biomolecular, Intrinsically unstructured domain, P53, Binding Sites, Transactivation domain, TFIIH, Sequence Homology, Amino Acid, Hematopoiesis, Terminal domain, Mutagenesis, Site-Directed, NMR structure, Transcriptional activators, Transcription factor, K562 Cells, Protein Binding, Transcription Factors
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