The N-terminal Helix-Turn-Helix Motif of Transcription Factors MarA and Rob Drives DNA Recognition
Corbella, Marina ; Liao, Qinghua ; Moreira, Cátia ; Parracino, Antonietta ; Kasson, Peter M and Kamerlin, Shina Caroline Lynn LU
(2021)
In The Journal of Physical Chemistry Part B
125(25).
p.6791-6806
- Abstract
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... (More)
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-dependent changes in 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 demonstrate that an acidic C-terminal loop of Rob can control the DNA binding mode, facilitating interconversion between the distinct DNA binding modes observed in MarA and Rob. In doing so, we provide detailed molecular insight into DNA binding and recognition by these proteins, which in turn is an important step toward the efficient design of antivirulence agents that target these proteins.
(Less)
- author
- Corbella, Marina
; Liao, Qinghua
; Moreira, Cátia
; Parracino, Antonietta
; Kasson, Peter M
and Kamerlin, Shina Caroline Lynn
LU
- publishing date
- 2021-07-01
- type
- Contribution to journal
- publication status
- published
- keywords
- Bacterial Proteins, Binding Sites, DNA/genetics, DNA-Binding Proteins/genetics, Escherichia coli/genetics, Escherichia coli Proteins/genetics, Helix-Turn-Helix Motifs, Trans-Activators/metabolism, Transcription Factors/genetics
- in
- The Journal of Physical Chemistry Part B
- volume
- 125
- issue
- 25
- pages
- 16 pages
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- pmid:34137249
- scopus:85110202194
- ISSN
- 1520-5207
- DOI
- 10.1021/acs.jpcb.1c00771
- language
- English
- LU publication?
- no
- id
- 76ef51cf-542b-417b-9f84-bcf0c6e7d919
- date added to LUP
- 2025-01-11 18:50:42
- date last changed
- 2025-05-04 17:25:59
@article{76ef51cf-542b-417b-9f84-bcf0c6e7d919,
abstract = {{<p>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-dependent changes in 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 demonstrate that an acidic C-terminal loop of Rob can control the DNA binding mode, facilitating interconversion between the distinct DNA binding modes observed in MarA and Rob. In doing so, we provide detailed molecular insight into DNA binding and recognition by these proteins, which in turn is an important step toward the efficient design of antivirulence agents that target these proteins.</p>}},
author = {{Corbella, Marina and Liao, Qinghua and Moreira, Cátia and Parracino, Antonietta and Kasson, Peter M and Kamerlin, Shina Caroline Lynn}},
issn = {{1520-5207}},
keywords = {{Bacterial Proteins; Binding Sites; DNA/genetics; DNA-Binding Proteins/genetics; Escherichia coli/genetics; Escherichia coli Proteins/genetics; Helix-Turn-Helix Motifs; Trans-Activators/metabolism; Transcription Factors/genetics}},
language = {{eng}},
month = {{07}},
number = {{25}},
pages = {{6791--6806}},
publisher = {{The American Chemical Society (ACS)}},
series = {{The Journal of Physical Chemistry Part B}},
title = {{The N-terminal Helix-Turn-Helix Motif of Transcription Factors MarA and Rob Drives DNA Recognition}},
url = {{http://dx.doi.org/10.1021/acs.jpcb.1c00771}},
doi = {{10.1021/acs.jpcb.1c00771}},
volume = {{125}},
year = {{2021}},
}