Flexibility of flanking DNA is a key determinant of transcription factor affinity for the core motif

Ghoshdastidar, D and Bansal, M (2022) Flexibility of flanking DNA is a key determinant of transcription factor affinity for the core motif. In: Biophysical Journal .

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Abstract

Selective gene regulation is mediated by recognition of specific DNA sequences by transcription factors (TFs). The extremely challenging task of searching out specific cognate DNA binding sites among several million putative sites within the eukaryotic genome is achieved by complex molecular recognition mechanisms. Elements of this recognition code include the core binding sequence, the flanking sequence context, and the shape and conformational flexibility of the composite binding site. To unravel the extent to which DNA flexibility modulates TF binding, in this study, we employed experimentally guided molecular dynamics simulations of ternary complex of closely related Hox heterodimers Exd-Ubx and Exd-Scr with DNA. Results demonstrate that flexibility signatures embedded in the flanking sequences impact TF binding at the cognate binding site. A DNA sequence has intrinsic shape and flexibility features. While shape features are localized, our analyses reveal that flexibility features of the flanking sequences percolate several basepairs and allosterically modulate TF binding at the core. We also show that lack of flexibility in the motif context can render the cognate site resistant to protein-induced shape changes and subsequently lower TF binding affinity. Overall, this study suggests that flexibility-guided DNA shape, and not merely the static shape, is a key unexplored component of the complex DNA-TF recognition code.

Item Type:	Journal Article
Publication:	Biophysical Journal
Publisher:	Biophysical Society
Additional Information:	The copyright for this article belongs to Biophysical Society.
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	05 Oct 2022 09:39
Last Modified:	05 Oct 2022 09:39
URI:	https://eprints.iisc.ac.in/id/eprint/77062

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