About: Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating Activity of SARS-CoV Papain-Like Protease

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About: Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating Activity of SARS-CoV Papain-Like Protease Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : wasabi.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating Activity of SARS-CoV Papain-Like Protease
Creator	Mesecar, Andrew Ratia, Kiira Baker, Susan Kilianski, Andrew Baez-Santos, Yahira
Source	Medline; PMC
abstract	Severe acute respiratory syndrome coronavirus (SARS-CoV) encodes a papain-like protease (PLpro) with both deubiquitinating (DUB) and deISGylating activities that are proposed to counteract the post-translational modification of signaling molecules that activate the innate immune response. Here we examine the structural basis for PLpro's ubiquitin chain and interferon stimulated gene 15 (ISG15) specificity. We present the X-ray crystal structure of PLpro in complex with ubiquitin-aldehyde and model the interaction of PLpro with other ubiquitin-chain and ISG15 substrates. We show that PLpro greatly prefers K48- to K63-linked ubiquitin chains, and ISG15-based substrates to those that are mono-ubiquitinated. We propose that PLpro's higher affinity for K48-linked ubiquitin chains and ISG15 stems from a bivalent mechanism of binding, where two ubiquitin-like domains prefer to bind in the palm domain of PLpro with the most distal ubiquitin domain interacting with a “ridge” region of the thumb domain. Mutagenesis of residues within this ridge region revealed that these mutants retain viral protease activity and the ability to catalyze hydrolysis of mono-ubiquitin. However, a select number of these mutants have a significantly reduced ability to hydrolyze the substrate ISG15-AMC, or be inhibited by K48-linked diubuiquitin. For these latter residues, we found that PLpro antagonism of the nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) signaling pathway is abrogated. This identification of key and unique sites in PLpro required for recognition and processing of diubiquitin and ISG15 versus mono-ubiquitin and protease activity provides new insight into ubiquitin-chain and ISG15 recognition and highlights a role for PLpro DUB and deISGylase activity in antagonism of the innate immune response.
has issue date	2014-05-22(xsd:dateTime)
bibo:doi	10.1371/journal.ppat.1004113
bibo:pmid	24854014
has license	cc-by
sha1sum (hex)	b7b6bf20c919a0b200c528e76f76f508d5554700
schema:url	https://doi.org/10.1371/journal.ppat.1004113
resource representing a document's title	Structural Basis for the Ubiquitin-Linkage Specificity and deISGylating Activity of SARS-CoV Papain-Like Protease
has PubMed Central identifier	PMC4031219
has PubMed identifier	24854014
schema:publication	PLoS Pathog
resource representing a document's body	covid:b7b6bf20c919a0b200c528e76f76f508d5554700#body_text
is schema:about of	named entity 'BINDING' named entity 'PROVIDES' named entity 'B-CELLS' named entity 'X-RAY' named entity 'SEVERE ACUTE RESPIRATORY SYNDROME CORONAVIRUS' named entity 'PRESENT' named entity 'POST-TRANSLATIONAL MODIFICATION' named entity 'ACTIVATE' named entity 'NUMBER OF' named entity 'HAVE' named entity 'AMC' named entity 'LIKE' named entity 'MONO' named entity 'COMPLEX' named entity 'BASED' named entity 'MUTAGENESIS' named entity 'HIGHER' named entity 'RIDGE' named entity 'SPECIFICITY' named entity 'UNIQUE' named entity 'CHAIN' named entity 'MECHANISM' named entity 'PROTEASE ACTIVITY' named entity 'NEW' named entity '10%' named entity 'INTERACTING' named entity 'THE THUMB' named entity 'LINKAGE' named entity 'processing' named entity '2014' named entity 'complex' named entity 'signaling molecules' named entity 'specificity' named entity 'ability' named entity 'domain' named entity 'DUB' named entity 'ubiquitin' named entity 'BASIS' named entity 'ACTIVITY' named entity 'DEUBIQUITINATING' named entity 'NUCLEAR' named entity '27S' named entity 'RETAIN' named entity 'SIGNALING MOLECULES' named entity 'UBIQUITINATED' named entity 'UBIQUITIN' named entity 'IDENTIFICATION' named entity 'REDUCED' named entity 'THESE' named entity 'DUB' named entity 'REGION' named entity 'PROPOSED' named entity 'STEMS' named entity 'ANTAGONISM' named entity 'STRUCTURAL' named entity 'SIGNALING PATHWAY' named entity 'VIRAL' named entity 'LINKAGE' named entity 'LIGHT' named entity 'MODEL' named entity 'INSIGHT' named entity 'SUBSTRATE' named entity 'HYDROLYSIS' named entity 'REQUIRED' named entity 'PAPAIN' named entity 'UBIQUITIN' named entity 'SPECIFICITY' named entity 'SARS-COV' named entity 'STRUCTURAL' named entity 'ACTIVITIES' named entity 'CRYSTAL STRUCTURE' named entity 'K63' named entity 'DOMAIN' named entity 'ACTIVATED' named entity 'DISTAL' named entity 'HERE' named entity 'KEY'

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