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The N-Terminal Helix-Turn-Helix Motif of Transcription Factors MarA and Rob Drives DNA Recognition

preprint
submitted on 25.04.2020 and posted on 27.04.2020 by Marina Corbella, Qinghua Liao, Peter M. Kasson, Shina Caroline Lynn Kamerlin

DNA-binding proteins play an important role in gene regulation and cellular function. The transcription factors MarA and Rob are two homologous members of the AraC/XylS family that regulate multidrug resistance. They share a common DNA-binding domain, and Rob possesses an additional C-terminal domain that permits binding of low-molecular weight effectors. Both proteins possess two helix-turn- helix (HTH) motifs capable of binding DNA; however, while MarA interacts with its promoter through both HTH-motifs, prior studies indicate that Rob binding to DNA via a single HTH-motif is sufficient for tight binding. In the present work, we perform microsecond time scale all-atom simulations of the binding of both transcription factors to different DNA sequences to understand the determinants of DNA recognition and binding. Our simulations characterize sequence-specific changes in the dynamical behavior upon DNA binding, showcasing the role of Arg40 of the N-terminal HTH-motif in allowing for specific tight binding. Finally, our simulations explain how an acidic C-terminal loop of Rob can control DNA binding mode. In doing so, we provide detailed molecular insight into DNA binding and recognition by these proteins, which in turn is an important step towards the efficient design of anti-virulence agents that target these proteins.

Funding

Vetenskapsrådet

Knut and Alice Wallenberg Foundation

SNIC 2.0: Swedish National Infrastructure for Computing

Swedish Research Council

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History

Email Address of Submitting Author

lynn.kamerlin@kemi.uu.se

Institution

Uppsala University

Country

Sweden

ORCID For Submitting Author

0000-0002-3190-1173

Declaration of Conflict of Interest

No conflict of interest.

Version Notes

Version 1.0.

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