Crystal structure and biochemical activity of the macro domain from rubella virus p150

Author:

Stoll Guido A.ORCID,Zhang Liao,Modis YorgoORCID

Abstract

ABSTRACTRubella virus remains a global health threat. Rubella infections during pregnancy can cause serious congenital pathology and no antiviral treatments are available. Rubella virus encodes a nonstructural polyprotein with RNA polymerase, methyltransferase, and papain-like cysteine protease activities, along with a putative macro domain of unknown function. Macro domains bind ADP-ribose adducts, a post-translational modification that plays a key role in host-virus conflicts. Some macro domains can also remove the mono-ADP-ribose adduct or degrade poly-ADP-ribose chains. Here, we report high-resolution crystal structures of the macro domain from rubella virus nonstructural protein p150, with and without ADP-ribose bound. The overall fold is most similar to macroD-type macro domains from various nonviral species. The specific composition and structure of the residues that poised for catalysis or coordinate ADP-ribose in the rubella virus macro domain are most similar to those of macro domains from alphaviruses. Isothermal calorimetry and enzymatic assays show that the rubella virus macro domain binds ADP-ribose in solution and has mono-ADP-ribosylhydrolase (de-MARylation) activity.IMPORTANCEOur work demonstrates that, like alpha- and coronaviruses, rubiviruses encode a mono-ADP-ribosylhydrolase with a structurally conserved macro domain fold to counteract MARylation by 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.

Publisher

Cold Spring Harbor Laboratory

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