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Nat Struct Mol Biol. 2019 Nov;26(11):1035-1043. doi: 10.1038/s41594-019-0321-z. Epub 2019 Nov 4.

Multiple direct interactions of TBP with the MYC oncoprotein.

Author information

1
Department of Physics, Chemistry, and Biology, Linköping University, Linköping, Sweden.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
3
Structural Genomics Consortium, Toronto, Ontario, Canada.
4
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
5
Molecular and Cellular Biology Laboratory, Graduate School of Medical Life Science, Yokohama City University, Yokohama, Kanagawa, Japan.
6
Department of Chemistry and Biochemistry, University of Windsor, Windsor, Ontario, Canada.
7
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. Linda.Penn@uhnresearch.ca.
8
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Linda.Penn@uhnresearch.ca.
9
Department of Physics, Chemistry, and Biology, Linköping University, Linköping, Sweden. maria.sunnerhagen@liu.se.

Abstract

Transcription factor c-MYC is a potent oncoprotein; however, the mechanism of transcriptional regulation via MYC-protein interactions remains poorly understood. The TATA-binding protein (TBP) is an essential component of the transcription initiation complex TFIID and is required for gene expression. We identify two discrete regions mediating MYC-TBP interactions using structural, biochemical and cellular approaches. A 2.4 -Å resolution crystal structure reveals that human MYC amino acids 98-111 interact with TBP in the presence of the amino-terminal domain 1 of TBP-associated factor 1 (TAF1TAND1). Using biochemical approaches, we have shown that MYC amino acids 115-124 also interact with TBP independently of TAF1TAND1. Modeling reveals that this region of MYC resembles a TBP anchor motif found in factors that regulate TBP promoter loading. Site-specific MYC mutants that abrogate MYC-TBP interaction compromise MYC activity. We propose that MYC-TBP interactions propagate transcription by modulating the energetic landscape of transcription initiation complex assembly.

PMID:
31686052
DOI:
10.1038/s41594-019-0321-z

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