7WFC

X-ray structure of HKU1-PLP2(Cys109Ser) catalytic mutant in complex with free ubiquitin

Summary for 7WFC

• Entry DOI: 10.2210/pdb7wfc/pdb
• Descriptor: Papain-like protease, 60S ribosomal protein L40, ZINC ION, ... (5 entities in total)
• Functional Keywords: hku1-plp2-ub complex, hydrolase
• Biological source: Human coronavirus HKU1; More
• Total number of polymer chains: 2
• Total formula weight: 43726.57

Authors

Xiong, Y.X.,Fu, Z.Y.,Huang, H. (deposition date: 2021-12-26, release date: 2022-12-28, Last modification date: 2023-11-29)

Primary citation

Xiong, Y.,Huang, B.,Yang, Y.,Fu, X.,Fu, Z.,Xu, H.,Liu, M.,Cao, D.,Zhang, M.,Yang, H.,Niu, X.,Yu, C.,Huang, H.
The substrate selectivity of papain-like proteases from human-infecting coronaviruses correlates with innate immune suppression.
Sci.Signal., 16:eade1985-eade1985, 2023

PubMed Abstract: Coronaviruses that can infect humans can cause either common colds (HCoV-NL63, HCoV-229E, HCoV-HKU1, and HCoV-OC43) or severe respiratory symptoms (SARS-CoV-2, SARS-CoV, and MERS-CoV). The papain-like proteases (PLPs) of SARS-CoV, SARS-CoV-2, MERS-CoV, and HCoV-NL63 function in viral innate immune evasion and have deubiquitinating (DUB) and deISGylating activities. We identified the PLPs of HCoV-229E, HCoV-HKU1, and HCoV-OC43 and found that their enzymatic properties correlated with their ability to suppress innate immune responses. A conserved noncatalytic aspartic acid residue was critical for both DUB and deISGylating activities, but the PLPs had differing ubiquitin (Ub) chain cleavage selectivities and binding affinities for Ub, K48-linked diUb, and interferon-stimulated gene 15 (ISG15) substrates. The crystal structure of HKU1-PLP2 in complex with Ub revealed binding interfaces that accounted for the unusually high binding affinity between this PLP and Ub. In cellular assays, the PLPs from the severe disease-causing coronaviruses strongly suppressed innate immune IFN-I and NF-κB signaling and stimulated autophagy, whereas the PLPs from the mild disease-causing coronaviruses generally showed weaker effects on immune suppression and autophagy induction. In addition, a PLP from a SARS-CoV-2 variant of concern showed increased suppression of innate immune signaling pathways. Overall, these results demonstrated that the DUB and deISGylating activities and substrate selectivities of these PLPs differentially contribute to viral innate immune evasion and may affect viral pathogenicity.

PubMed: 37130166
DOI: 10.1126/scisignal.ade1985

Experimental method

X-RAY DIFFRACTION (2.6 Å)