Macro1 domain residue F156: A hallmark of SARS-CoV-2 de-MARylation specificity

Oney Ortega Granda (1) , Karine Alvarez (1) , Maria J Mate-Perez (1) , Bruno Canard (1) , François Ferron (1) , Nadia Rabah (1)

1 AFMB - Architecture et fonction des macromolécules biologiques

SARS-CoV-2 is a large, enveloped and positive sense single stranded RNA virus. Its genome codes for 16 non-structural proteins. The largest protein of this complex is nsp3, that contains a well conserved Macro1 domain. Viral Macro domains were shown to bind to mono-ADP-ribose (MAR) and poly-ADP-ribose (PAR) in their free form or conjugated to protein substrates. They carry ADPribose hydrolase activities implicated in the regulation of innate immunity. SARS-CoV-2 and SARS-CoV show widely different induction and handling of the host interferon response. Herein, we have conducted a mutational study on the key amino-acid residue F156 in SARS-CoV-2, pinpointed by bioinformatic and structural studies, and its cognate residue N157 in SARS-CoV. Our data suggest that the exchange of these residues slightly modifies ADP-ribose binding, but drastically impacts de-MARylation activity. Alanine substitutions at this position hampers PAR binding, abolishes MAR hydrolysis of SARS-CoV-2, and reduces by 70% this activity in the case of SARS-CoV.

Mots clés: SARS-CoV-2; Macro domain; ADP-ribose; de-MARylation; ADP-ribose binding

Domaines: Virologie; Maladies émergentes; Maladies infectieuses

Oney Ortega Granda, Karine Alvarez, Maria J Mate-Perez, Bruno Canard, François Ferron, et al.. Macro1 domain residue F156: A hallmark of SARS-CoV-2 de-MARylation specificity. Virology, 2023, 587, pp.109845. ⟨10.1016/j.virol.2023.109845⟩. ⟨hal-04199059⟩