creators_name: Deep, Amar
creators_name: Singh, Latika
creators_name: Kaur, Japleen
creators_name: Velusamy, Maheshwaran
creators_name: Bhardwaj, Pushpanjali
creators_name: Singh, Ramandeep
creators_name: Thakur, Krishan Gopal
type: article
datestamp: 2024-07-16 04:16:43
lastmod: 2024-07-16 04:16:43
metadata_visibility: show
title: Structural insights into DarT toxin neutralization by cognate DarG antitoxin: ssDNA mimicry by DarG C-terminal domain keeps the DarT toxin inhibited

ispublished: pub
subjects: QR
keywords: DNA mimic; DNA modification; DNA ribosylation; DarTG; Mycobacterium tuberculosis; toxin-antitoxin system; toxin-binding domain
note: The copyright of this article belongs to Cell Press/Science Direct
abstract: 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.


date: 2023-07-06
date_type: published
publication: Structure (London, England : 1993)
volume: 31
number: 7
publisher: Cell Press/Science Direct
pagerange: 780-789
id_number: 10.1016/j.str.2023.04.008
refereed: TRUE
issn: 1878-4186
official_url: https://www.sciencedirect.com/science/article/pii/S0969212623001314?via%3Dihub
citation:   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