Crystal structure and biochemical activity of the macrodomain from rubella virus p150
(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.
(Less)
- author
- Stoll, Guido A ; Nikolopoulos, Nikos ; Zhai, Haoming ; Zhang, Liao ; Douse, Christopher H LU and Modis, Yorgo
- organization
- publishing date
- 2024
- 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}}, }