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

Oney Ortega Granda; Karine Alvarez; Maria J Mate-Perez; Bruno Canard; François Ferron; Nadia Rabah

doi:10.1016/j.virol.2023.109845

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

Virology. 2023 Oct:587:109845. doi: 10.1016/j.virol.2023.109845. Epub 2023 Jul 24.

Authors

Oney Ortega Granda¹, Karine Alvarez¹, Maria J Mate-Perez¹, Bruno Canard¹, François Ferron¹, Nadia Rabah²

Affiliations

¹ Aix Marseille Université, CNRS, AFMB UMR 7257, Marseille, France.
² Aix Marseille Université, CNRS, AFMB UMR 7257, Marseille, France; Previous Affiliation: Université de Toulon, 83130, La Garde, France. Electronic address: nadia.rabah@univ-amu.fr.

PMID: 37517331
DOI: 10.1016/j.virol.2023.109845

Abstract

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 ADP-ribose 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.

Keywords: ADP-ribose; ADP-ribose binding; Macro domain; SARS-CoV-2; de-MARylation.