Mechanistic insights into COVID-19 by global analysis of the SARS-CoV-2 3CL^pro substrate degradome.

ABSTRACT: The main viral protease (3CL^pro) is indispensable for SARS-CoV-2 replication. We delineate the human protein substrate landscape of 3CL^pro by TAILS substrate-targeted N-terminomics. We identify more than 100 substrates in human lung and kidney cells supported by analyses of SARS-CoV-2-infected cells. Enzyme kinetics and molecular docking simulations of 3CL^pro engaging substrates reveal how noncanonical cleavage sites, which diverge from SARS-CoV, guide substrate specificity. Cleaving the interactors of essential effector proteins, effectively stranding them from their binding partners, amplifies the consequences of proteolysis. We show that 3CL^pro targets the Hippo pathway, including inactivation of MAP4K5, and key effectors of transcription, mRN

SUBMITTER: Pablos I 

PROVIDER: S-EPMC8501228 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature