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Crystal structure and biochemical activity of the macrodomain from rubella virus p150

Stoll, Guido A ; Nikolopoulos, Nikos ; Zhai, Haoming ; Zhang, Liao ; Douse, Christopher H LU and Modis, Yorgo (2024) In Journal of Virology 98(2). p.1-17
Abstract

Rubella virus encodes a nonstructural polyprotein with RNA polymerase, methyltransferase, and papain-like cysteine protease activities, along with a putative macrodomain of unknown function. Macrodomains bind ADP-ribose adducts, a post-translational modification that plays a key role in host-virus conflicts. Some macrodomains can also remove the mono-ADP-ribose adduct or degrade poly-ADP-ribose chains. Here, we report high-resolution crystal structures of the macrodomain from rubella virus nonstructural protein p150, with and without ADP-ribose binding. The overall fold is most similar to macroD-type macrodomains from various nonviral species. The specific composition and structure of the residues that coordinate ADP-ribose in the... (More)

Rubella virus encodes a nonstructural polyprotein with RNA polymerase, methyltransferase, and papain-like cysteine protease activities, along with a putative macrodomain of unknown function. Macrodomains bind ADP-ribose adducts, a post-translational modification that plays a key role in host-virus conflicts. Some macrodomains can also remove the mono-ADP-ribose adduct or degrade poly-ADP-ribose chains. Here, we report high-resolution crystal structures of the macrodomain from rubella virus nonstructural protein p150, with and without ADP-ribose binding. The overall fold is most similar to macroD-type macrodomains from various nonviral species. The specific composition and structure of the residues that coordinate ADP-ribose in the rubella virus macrodomain are most similar to those of macrodomains from alphaviruses. Isothermal calorimetry shows that the rubella virus macrodomain binds ADP-ribose in solution. Enzyme assays show that the rubella virus macrodomain can hydrolyze both mono- and poly-ADP-ribose adducts. Site-directed mutagenesis identifies Asn39 and Cys49 required for mono-ADP-ribosylhydrolase (de-MARylation) activity.IMPORTANCERubella virus remains a global health threat. Rubella infections during pregnancy can cause serious congenital pathology, for which no antiviral treatments are available. Our work demonstrates that, like alpha- and coronaviruses, rubiviruses encode a mono-ADP-ribosylhydrolase with a structurally conserved macrodomain fold to counteract MARylation by poly (ADP-ribose) polymerases (PARPs) in the host innate immune response. Our structural data will guide future efforts to develop novel antiviral therapeutics against rubella or infections with related viruses.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Virology
volume
98
issue
2
article number
e0177723
pages
1 - 17
publisher
American Society for Microbiology
external identifiers
  • scopus:85185614159
  • pmid:38289106
ISSN
1098-5514
DOI
10.1128/jvi.01777-23
language
English
LU publication?
yes
id
be45b16e-ae8f-44d1-bf9c-16712c479367
date added to LUP
2024-02-06 18:57:24
date last changed
2024-04-24 14:48:46
@article{be45b16e-ae8f-44d1-bf9c-16712c479367,
  abstract     = {{<p>Rubella virus encodes a nonstructural polyprotein with RNA polymerase, methyltransferase, and papain-like cysteine protease activities, along with a putative macrodomain of unknown function. Macrodomains bind ADP-ribose adducts, a post-translational modification that plays a key role in host-virus conflicts. Some macrodomains can also remove the mono-ADP-ribose adduct or degrade poly-ADP-ribose chains. Here, we report high-resolution crystal structures of the macrodomain from rubella virus nonstructural protein p150, with and without ADP-ribose binding. The overall fold is most similar to macroD-type macrodomains from various nonviral species. The specific composition and structure of the residues that coordinate ADP-ribose in the rubella virus macrodomain are most similar to those of macrodomains from alphaviruses. Isothermal calorimetry shows that the rubella virus macrodomain binds ADP-ribose in solution. Enzyme assays show that the rubella virus macrodomain can hydrolyze both mono- and poly-ADP-ribose adducts. Site-directed mutagenesis identifies Asn39 and Cys49 required for mono-ADP-ribosylhydrolase (de-MARylation) activity.IMPORTANCERubella virus remains a global health threat. Rubella infections during pregnancy can cause serious congenital pathology, for which no antiviral treatments are available. Our work demonstrates that, like alpha- and coronaviruses, rubiviruses encode a mono-ADP-ribosylhydrolase with a structurally conserved macrodomain fold to counteract MARylation by poly (ADP-ribose) polymerases (PARPs) in the host innate immune response. Our structural data will guide future efforts to develop novel antiviral therapeutics against rubella or infections with related viruses.</p>}},
  author       = {{Stoll, Guido A and Nikolopoulos, Nikos and Zhai, Haoming and Zhang, Liao and Douse, Christopher H and Modis, Yorgo}},
  issn         = {{1098-5514}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{1--17}},
  publisher    = {{American Society for Microbiology}},
  series       = {{Journal of Virology}},
  title        = {{Crystal structure and biochemical activity of the macrodomain from rubella virus p150}},
  url          = {{http://dx.doi.org/10.1128/jvi.01777-23}},
  doi          = {{10.1128/jvi.01777-23}},
  volume       = {{98}},
  year         = {{2024}},
}