5w8u
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(New page: ==Crystal structure of MERS-CoV papain-like protease in complex with the C-terminal domain of human ISG15== <StructureSection load='5w8u' size='340' side='right' caption='5w8u, [[Reso...)
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Revision as of 09:17, 4 October 2017
proteopedia linkproteopedia linkCrystal structure of MERS-CoV papain-like protease in complex with the C-terminal domain of human ISG15
Structural highlights
Function[ISG15_HUMAN] Ubiquitin-like protein that is conjugated to intracellular target proteins after IFN-alpha or IFN-beta stimulation. Its enzymatic pathway is partially distinct from that of ubiquitin, differing in substrate specificity and interaction with ligating enzymes. ISG15 conjugation pathway uses a dedicated E1 enzyme, but seems to converge with the Ub conjugation pathway at the level of a specific E2 enzyme. Targets include STAT1, SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, EIF2AK2/PKR, MX1/MxA, and RIG-1. Deconjugated by USP18/UBP43. Shows specific chemotactic activity towards neutrophils and activates them to induce release of eosinophil chemotactic factors. May serve as a trans-acting binding factor directing the association of ligated target proteins to intermediate filaments. May also be involved in autocrine, paracrine and endocrine mechanisms, as in cell-to-cell signaling, possibly partly by inducing IFN-gamma secretion by monocytes and macrophages. Seems to display antiviral activity during viral infections.[1] [2] [3] [4] [5] [6] In response to IFN-tau secreted by the conceptus, may ligate to and regulate proteins involved in the release of prostaglandin F2-alpha (PGF), and thus prevent lysis of the corpus luteum and maintain the pregnancy (By similarity).[7] [8] [9] [10] [11] [12] Publication Abstract from PubMedMiddle East respiratory syndrome coronavirus (MERS-CoV) is an emerging human pathogen that is the causative agent for Middle East respiratory syndrome (MERS). With MERS outbreaks resulting in over 35% fatalities and now spread to 27 countries, MERS-CoV poses a significant on-going threat to global human health. As part of its viral genome, MERS-CoV encodes for a papain-like protease (PLpro) that has been observed to act as a deubiquitinase and deISGylase to antagonize IFN-I immune pathways. This activity is in addition to its viral polypeptide cleavage function. Although the overall impact of MERS-CoV PLpro function is observed to be essential, difficulty has been encountered in delineating the importance of its separate functions, particularly its deISGylase activity. As a result, the interface of MERS-CoV and human interferon stimulated gene product 15 (hISG15) was probed with isothermal calorimetry suggesting the C-terminal domain of hISG15 to be principally responsible for interactions. Subsequently, the structure of MERS-CoV PLpro was solved to 2.4 A in complex with the C-terminal domain of hISG15. Utilizing this structural information, mutants were generated that lacked appreciable deISGylase activity but retained wild-type deubiquitinase and peptide cleavage activities. Hence, this provides a new platform for understanding viral deISGylase activity within MERS-CoV and other CoVs.IMPORTANCE Coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV), encode a papain-like protease (PLpro) that possesses the ability to antagonize interferon immune pathways through the removal of ubiquitin and interferon-stimulated gene product 15 (ISG15) from target proteins. The lack of CoV proteases with attenuated deISGylase activity has been a key obstacle in delineating the impact between deubiquitinase and deISGylase activities on viral host evasion and pathogenesis. Here, biophysical techniques revealed that MERS-CoV PLpro chiefly engages human ISG15 occurs through its C-terminal domain. The first structure of MERS-CoV PLpro in complex with this domain exposed the interface between these two entities. Employing these structural insights, mutations were employed to selectively remove deISGylase activity with no appreciable impact to its other deubiquitinase and peptide cleavage biochemical properties. Excitingly, this study introduces a new tool to probe pathogenesis of MERS-CoV and related viruses through the removal of viral deISGylase activity. Structurally guided removal of deISGylase biochemical activity from papain-Like protease originating from the Middle East Respiratory Syndrome Virus.,Daczkowski CM, Goodwin O, Dzimianski JV, Farhat JJ, Pegan SD J Virol. 2017 Sep 20. pii: JVI.01067-17. doi: 10.1128/JVI.01067-17. PMID:28931677[13] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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