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Title: Recognition of Lys48-Linked Di-ubiquitin and Deubiquitinating Activities of the SARS Coronavirus Papain-like Protease

Journal Article · · Molecular Cell
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Deubiquitinating enzymes (DUBs) recognize and cleave linkage-specific polyubiquitin (polyUb) chains, but mechanisms underlying specificity remain elusive in many cases. The severe acute respiratory syndrome (SARS) coronavirus papain-like protease (PLpro) is a DUB that cleaves ISG15, a two-domain Ub-like protein, and Lys48-linked polyUb chains, releasing diUbLys48 products. To elucidate this specificity, we report the 2.85 Å crystal structure of SARS PLpro bound to a diUbLys48 activity-based probe. SARS PLpro binds diUbLys48 in an extended conformation via two contact sites, S1 and S2, which are proximal and distal to the active site, respectively. We show that specificity for polyUbLys48 chains is predicated on contacts in the S2 site and enhanced by an S1-S1' preference for a Lys48 linkage across the active site. In contrast, ISG15 specificity is dominated by contacts in the S1 site. Determinants revealed for polyUbLys48 specificity should prove useful in understanding PLpro deubiquitinating activities in coronavirus infections.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC); National Institutes of Health (NIH); National Inst. of General Medical Sciences (NIGMS); National Cancer Inst.; NYU Laura & Isaac Perlmutter Cancer Center Support Grant’s Developmental Project Program; NWO-VENI
Grant/Contract Number:
AC02-06CH11357; P41 GM103403; F32GM100598; GM084244; ES025166; GM065872; P30 CA008748; P30 CA016087; 722.014.002; 281699
OSTI ID:
1357829
Alternate ID(s):
OSTI ID: 1256348; OSTI ID: 1326434
Journal Information:
Molecular Cell, Journal Name: Molecular Cell Vol. 62 Journal Issue: 4; ISSN 1097-2765
Publisher:
Cell Press - ElsevierCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 97 works
Citation information provided by
Web of Science

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