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Publication Abstract from PubMed

DNA binding by the ETS transcriptional repressor ETV6 (or TEL) is auto-inhibited~50-fold due to an alpha-helix that sterically blocks its ETS domain binding interface. Using NMR spectroscopy, we demonstrate that this marginally-stable helix is unfolded, and not displaced to a non-inhibitory position, when ETV6 is bound to DNA containing a consensus 5'GGAA3' recognition site. Although significantly lower in affinity, binding to non-specific DNA is auto-inhibited~5-fold and also accompanied by helix unfolding. Based on NMR chemical shift perturbations, both specific and non-specific DNA are bound via the same canonical ETS domain interface. However, spectral perturbations are smaller for the non-specific complex, suggesting weaker and less well-defined interactions than in the specific complex. In parallel, the crystal structure of ETV6 bound to a specific DNA duplex was determined. The structure of this complex reveals that a non-conserved histidine residue in the ETS domain recognition helix helps establish the specificity of ETV6 for DNA-binding sites containing 5'GGAA3' versus 5'GGAT3'. These studies provide a unified steric mechanism for attenuating ETV6 binding to both specific and non-specific DNA and expand the repertoire of characterized auto-inhibitory strategies utilized to regulate ETS factors.

Steric mechanism of auto-inhibitory regulation of specific and non-specific DNA binding by the ETS transcriptional repressor ETV6.,De S, Chan AC, Coyne HJ 3rd, Bhachech N, Hermsdorf U, Okon M, Murphy ME, Graves BJ, McIntosh LP J Mol Biol. 2013 Dec 11. pii: S0022-2836(13)00747-X. doi:, 10.1016/j.jmb.2013.11.031. PMID:24333486^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.