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

Publication date: Jan 30, 2024

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.

Concepts Keywords
Antiviral ADP ribosylation
Coronaviruses ADPÔÇôribose
Cys49 alphavirus
Host de-MARylase
Ribosylhydrolase de-MARylation
enzymes
macrodomain
mono-ADP-ribosylhydrolase
rubella virus
X-ray crystallography

Semantics

Type Source Name
disease VO Rubella virus
pathway KEGG RNA polymerase
drug DRUGBANK Papain
drug DRUGBANK L-Cysteine
disease IDO host
disease VO report
disease IDO site
disease MESH Rubella
disease MESH infections
disease IDO innate immune response
disease VO Viruses
disease VO Alphavirus

Original Article

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