Auto-inhibition of ETV6 (TEL) DNA-binding: appended helices sterically block the ETS domain

ETV6 (or TEL), a transcriptional repressor belonging to the ETS family, is frequently involved in chromosomal translocations linked with human cancers. It displays a DNA-binding mode distinct from other ETS proteins due to the presence of a self-associating PNT domain. In this study, we used NMR spe...

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Veröffentlicht in:Journal of molecular biology 2012-05, Vol.421 (1), p.67-84
Hauptverfasser: Coyne, H. Jerome, De, Soumya, Okon, Mark, Green, Sean M., Bhachech, Niraja, Graves, Barbara J., McIntosh, Lawrence P.
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Sprache:eng
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Zusammenfassung:ETV6 (or TEL), a transcriptional repressor belonging to the ETS family, is frequently involved in chromosomal translocations linked with human cancers. It displays a DNA-binding mode distinct from other ETS proteins due to the presence of a self-associating PNT domain. In this study, we used NMR spectroscopy to dissect the structural and dynamic bases for the auto-inhibition of ETV6 DNA-binding by sequences C-terminal to its ETS domain. The CID (C-terminal inhibitory domain) contains two helices, H4 and H5, which sterically block the DNA-binding interface of the ETS domain. Importantly, these appended helices are only marginally stable as revealed by amide hydrogen exchange and 15 N relaxation measurements. The CID is thus poised to undergo a facile conformational change as required for DNA-binding. The CID also dampens millisecond timescale motions of the ETS domain hypothesized to be critical for the recognition of specific ETS target sequences. This work illustrates the use of appended sequences on conserved structural domains to generate biological diversity, and complements previous studies of the allosteric mechanism of ETS1 auto-inhibition to reveal both common and divergent features underlying the regulation of DNA-binding by ETS transcription factors.
ISSN:0022-2836
1089-8638
DOI:10.1016/j.jmb.2012.05.010