Expanding our understanding of the role polyprotein conformation plays in the coronavirus life cycle

Abstract

Coronavirus are the causative agents in many globally concerning respiratory disease outbreaks such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS) and coronavirus disease-2019 (COVID-19). It is therefore important that we improve our understanding of how the molecular components of the virus facilitate the viral life cycle. These details will allow for the design of effective interventions. Krichel and coauthors in their article in the Biochemical Journal provide molecular details of how the viral polyprotein (nsp7-10) produced from the positive single stranded RNA genome, is cleaved to form proteins that are part of the replication/transcription complex. The authors highlight the impact the polyprotein conformation has on the cleavage efficiency of the main protease (Mpro) and hence the order of release of non-structural proteins 7-10 (nsp7-10) of the SARS-CoV. Cleavage order is important in controlling viral processes and seems to have relevance in terms of the protein-protein complexes formed. The authors made use of mass spectrometry to advance our understanding of the mechanism by which coronaviruses control nsp 7, 8, 9 and 10 production in the virus life cycle.

Keywords: Coronavirus; SARS-CoV; nsp7–10; polyprotein 1a/ab; polyprotein conformation; posttranslational control.

Figure 1.. Polyprotein nsp7–10 cleavage order and protein product structures.

Krichel and coauthors [6] indicated that conformation of the nsp7–10 polyprotein resulted in nsp's being cleaved from the polyprotein by M^pro (PDB code 1UK3 [8]—purple) in order; nsp10 then nsp9 then nsp8 from nsp7. Structures available for the nsp's are depicted as ribbon structures visualized using Discovery Studio software version 19.1.0.18287 (Accelrys, San Diego, U.S.A.) in corresponding colors. Blue represents nsp10, the dodecamer structure (PDB 2G9T) [11] as well as monomer structure (PDB 2FYG) [12]. Green represents nsp9, the dimer structure (PDB 1QZ8) [14]. Yellow represents nsp8 and red represents nsp7 with hexadecamer (PDB 2AHM) [15] and heterotrimer (PDB 3UB0) [10] structures. Krichel and coauthors also reported a potential hetero-tetramer (nsp7:nsp8 2:2) which indicates more protein complexes could be present.