Nonstructural protein 15 – endoRNAse
Nsp15 is a Nidoviral RNA uridylate-specific endoribonuclease and its C-terminal is a catalytic domain belonging to the EndoU family of enzymes. Within SARS-CoV-1 and -CoV-2, nsp15 is very conserved (89 % identity).
Narrative
Nsp15 is a Nidoviral RNA uridylate-specific endoribonuclease (NendoU) and its C-terminal is a catalytic domain belonging to the EndoU family of enzymes (Kim et al. 2020; Johnson et al. 2010; Perlman 2011). EndoU enzymes have RNA endonuclease activity producing 2’-3’ cyclic phosphodiester and 5’-hydroxyl termini (Ulferts and Ziebuhr 2011). A study in 2017 proposed that the NendoU activity interferes with the innate immune response (Deng et al. 2017), however this finding was disputed in a 2019 study (Liu et al. 2019) that showed that the interference was independent of the endonuclease activity.
Structural analysis and comparison with SARS-CoV-1 nsp15 – The nsp15 monomer (346 a.a.) forms hexamers. Each monomer consists of three domains, namely the N-terminal, middle domain, and catalytic NendoU domain at the C-terminal (Kim et al. 2020). Within SARS-CoV-1 and SARS-CoV-2, nsp15 is very conserved (89% identity). However, the recently solved crystal structure of the nsp15 monomer, shows a significant conformational variation in the region of the catalytic site. Although several non-conservative substitutions occur around this region, the conformation of the catalytic loop (a.a. 234-249) is known to greatly change upon protein oligomerization.