Abstract
The general transcription factor IID (TFIID) initiates RNA polymerase II-mediated eukaryotic transcription by nucleating pre-initiation complex formation at the core promoter of protein-encoding genes. TAF1, the largest integral subunit of TFIID, contains an evolutionarily conserved yet poorly characterized central core domain, whose specific mutation disrupts cell proliferation in the temperature-sensitive mutant hamster cell line ts13. Although the impaired TAF1 function in the ts13 mutant has been associated with defective transcriptional regulation of cell cycle genes, the mechanism by which TAF1 mediates transcription as part of TFIID remains unclear. Here, we present the crystal structure of the human TAF1 central core domain in complex with another conserved TFIID subunit, TAF7, which biochemically solubilizes TAF1. The TAF1-TAF7 complex displays an inter-digitated compact architecture, featuring an unexpected TAF1 winged helix (WH) domain mounted on top of a heterodimeric triple barrel. The single TAF1 residue altered in the ts13 mutant is buried at the junction of these two structural domains. We show that the TAF1 WH domain has intrinsic DNA-binding activity, which depends on characteristic residues that are commonly used by WH fold proteins for interacting with DNA. Importantly, mutations of these residues not only compromise DNA binding by TAF1, but also abrogate its ability to rescue the ts13 mutant phenotype. Together, our results resolve the structural organization of the TAF1-TAF7 module in TFIID and unveil a critical promoter-binding function of TAF1 in transcription regulation.
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Acknowledgements
We thank the beam line staff of the Advanced Light Source at the University of California at Berkeley for help with data collection, undergraduates E Larson and M Kufeld for assistance with the in vivo complementation experiments, and members of the Zheng and Wang laboratories for discussion. This work is supported by the Howard Hughes Medical Institute (NZ) and the University of Washington Royalty Research Fund (EHW).
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
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Supplementary information, Figure S1
Sequence alignment of representative eukaryotic TAF7 orthologs annotated with secondary structures. (PDF 160 kb)
Supplementary information, Figure S2
Sequence alignment of DUF3591 domains of representative eukaryotic TAF1 orthologs annotated with secondary structure labeled. (PDF 346 kb)
Supplementary information, Figure S3
Two salt bridges formed among three TAF7 β-hairpin residues are buried in the TAF1 barrel. (PDF 634 kb)
Supplementary information, Figure S4
A close-up view of the C-terminal residues in the TAF1 DUF3591 fragment together with positive Fo-Fc electron density contoured at 3.0 σ (red) and 2Fo-Fc electron density contoured at 1.0 σ (blue) calculated before the phosphate groups were built. (PDF 1170 kb)
Supplementary information, Figure S5
Structure comparison between the yeast HAT enzyme ESA1 and TAF1 in complex with TAF7. (PDF 1719 kb)
Supplementary information, Table S1
Summary of crystallographic information (PDF 114 kb)
Supplementary information, Table S2
Nucleic acid sequences of the probes used in EMSA analysis and the primers for the site mutagenesis (PDF 44 kb)
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Wang, H., Curran, E., Hinds, T. et al. Crystal structure of a TAF1-TAF7 complex in human transcription factor IID reveals a promoter binding module. Cell Res 24, 1433–1444 (2014). https://doi.org/10.1038/cr.2014.148
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DOI: https://doi.org/10.1038/cr.2014.148
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