期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 111, 期 30, 页码 11019-11024出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1401891111
关键词
transcription factor regulation; protein dynamics; intrinsically disordered region; fuzz complex
资金
- Canadian Cancer Society Research Institute [2011-700772]
- National Institutes of Health [R01 GM38663]
- Huntsman Cancer Institute/Huntsman Cancer Foundation
- Howard Hughes Medical Institute
- UBC
- CIHR Frederick-Banting Graduate Scholarship
The E26 transformation-specific (Ets-1) transcription factor is autoinhibited by a conformationally disordered serine-rich region (SRR) that transiently interacts with its DNA-binding ETS domain. In response to calcium signaling, autoinhibition is reinforced by calmodulin- dependent kinase II phosphorylation of serines within the SRR. Using mutagenesis and quantitative DNA-binding measurements, we demonstrate that phosphorylation-enhanced autoinhibition requires the presence of phenylalanine or tyrosine (phi) residues adjacent to the SRR phosphoacceptor serines. The introduction of additional phosphorylated Ser-phi-Asp, but not Ser-Ala-Asp, repeats within the SRR dramatically reinforces autoinhibition. NMR spectroscopic studies of phosphorylated and mutated SRR variants, both within their native context and as separate trans-acting peptides, confirmed that the aromatic residues and phosphoserines contribute to the formation of a dynamic complex with the ETS domain. Complementary NMR studies also identified the SRR-interacting surface of the ETS domain, which encompasses its positively charged DNA-recognition interface and an adjacent region of neutral polar and nonpolar residues. Collectively, these studies highlight the role of aromatic residues and their synergy with phosphoserines in an intrinsically disordered regulatory sequence that integrates cellular signaling and gene expression.
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