Evolutionary and molecular basis of ADP-ribosylation reversal by zinc-dependent macrodomains
Year: 2024
Type: article
Abstract: Dynamic ADP-ribosylation signaling is a crucial pathway that controls fundamental cellular processes, in particular, the response to cellular stresses such as DNA damage, reactive oxygen species, and infection. In some pathogenic microbes, the response to oxidative stress is controlled by a SirTM/zinc-containing macrodomain (Zn-Macro) pair responsible for establishment and removal of the modification, respectively. Targeting this defence mechanism against the host's innate immune response may lead to novel approaches to support the fight against emerging antimicrobial resistance. Earlier studies suggested that Zn-Macros play a key role in the activation of this defence. Therefore, we used phylogenetic, biochemical, and structural approaches to elucidate the functional properties of these enzymes. Using the substrate mimetic asparagine-ADP-ribose as well as the ADP-ribose product, we characterize the catalytic role of the zinc ion in the removal of the ADP-ribosyl modification. Furthermore, we determined structural properties that contribute to substrate selectivity within the different Zn-Macro branches. Together, our data not only give new insights into the Zn-Macro family but also highlight their distinct features that may be exploited for the development of future therapies.
Source: Journal of Biological Chemistry
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,800
Funders: Wellcome Trust, Diamond Light Source, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, University of Exeter, European Synchrotron Radiation Facility, China Scholarship Council, Medical Research Council Centre for Medical Mycology, Directorate for Biological Sciences, Medical Research Council, Biotechnology and Biological Sciences Research Council, NIHR Leicester Biomedical Research Centre
Awards: G1115001388, G1620553015, G1666550810, G230613184, G2311310010, Serine ADP-ribosylation in genome stability and human disease, MRC Centre for Medical Mycology, Reversible ADP-ribosylation signaling in the control of coronavirus infection, G370692677, G4057596614, ADP-ribosylation of DNA in Mycobacterium tuberculosis, G4584335570, G5066282738, G5129053096, G5309921416, G669361101, Control of genomic integrity and virulence of Aspergillus fumigatus by ADP-ribosylation., G7082300319, G7617489868, G7788528898, G8044389041, Medical Research Council Centre for Medical Mycology, Understanding the activity and role of DarTG, a toxin:antitoxin system responsible for a novel DNA modification, G8310141513, G8723269792, G8906178588
OpenAlex ID: W4402496084