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Structural insights into DarT toxin neutralization by cognate DarG antitoxin: ssDNA mimicry by DarG C-terminal domain keeps the DarT toxin inhibited

DIR@IMTECH: CSIR-Institute of Microbial Technology

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Title Structural insights into DarT toxin neutralization by cognate DarG antitoxin: ssDNA mimicry by DarG C-terminal domain keeps the DarT toxin inhibited
 
Creator Deep, Amar
Singh, Latika
Kaur, Japleen
Velusamy, Maheshwaran
Bhardwaj, Pushpanjali
Singh, Ramandeep
Thakur, Krishan Gopal
 
Subject QR Microbiology
 
Description In the DarTG toxin-antitoxin system, the DarT toxin ADP-ribosylates single-stranded DNA (ssDNA), which stalls DNA replication and plays a crucial role in controlling bacterial growth and bacteriophage infection. This toxic activity is reversed by the N-terminal macrodomain of the cognate antitoxin DarG. DarG also binds DarT, but the role of these interactions in DarT neutralization is unknown. Here, we report that the C-terminal domain of DarG (DarG toxin-binding domain [DarGTBD]) interacts with DarT to form a 1:1 stoichiometric heterodimeric complex. We determined the 2.2 Å resolution crystal structure of the Mycobacterium tuberculosis DarT-DarGTBD complex. The comparative structural analysis reveals that DarGTBD interacts with DarT at the DarT/ssDNA interaction interface, thus sterically occluding substrate ssDNA binding and consequently inactivating toxin by direct protein-protein interactions. Our data support a unique two-layered DarT toxin neutralization mechanism of DarG, which is important in keeping the toxin molecules in check under normal growth conditions.
 
Publisher Cell Press/Science Direct
 
Date 2023-07-06
 
Type Article
PeerReviewed
 
Relation https://www.sciencedirect.com/science/article/pii/S0969212623001314?via%3Dihub
http://crdd.osdd.net/open/3174/
 
Identifier Deep, Amar and Singh, Latika and Kaur, Japleen and Velusamy, Maheshwaran and Bhardwaj, Pushpanjali and Singh, Ramandeep and Thakur, Krishan Gopal (2023) Structural insights into DarT toxin neutralization by cognate DarG antitoxin: ssDNA mimicry by DarG C-terminal domain keeps the DarT toxin inhibited. Structure (London, England : 1993), 31 (7). pp. 780-789. ISSN 1878-4186