5tl7
Crystal structure of SARS-CoV papain-like protease in complex with C-terminal domain mouse ISG15
Structural highlights
FunctionISG15_MOUSE Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include SERPINA3G/SPI2A, JAK1, MAPK3/ERK1, PLCG1, TRIM25, STAT5A, MAPK1/ERK2 and globin. Can also isgylate: DDX58/RIG-I which inhibits its function in antiviral signaling response and EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A and B virus, sindbis virus (SV) and herpes simplex type-1 (HHV-1). Plays a significant role in the control of neonatal Chikungunya virus (CHIKV) infection by acting as a putative immunomodulator of proinflammatory cytokines. Protects mice against the consequences of Chikungunya virus infection by downregulating the pathogenic cytokine response, often denoted as the cytokine storm. Plays a role in erythroid differentiation. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity.[1] [2] [3] [4] [5] [6] [7] [8] Publication Abstract from PubMedSevere Acute and Middle East Respiratory syndrome coronaviruses (SARS-CoV and MERS-CoV) encode multifunctional papain-like proteases (PLPs) that have the ability to process the viral polyprotein to facilitate RNA replication as well as antagonize the host innate-immune response. The latter function involves reversing post-translational modification of cellular proteins conjugated with either ubiquitin (Ub) or Ub-like interferon stimulated gene product 15 (ISG15). Ubiquitin is known to be highly conserved among eukaryotes but surprisingly ISG15 is highly divergent among animals. The ramifications of this sequence divergence to recognition of ISG15 by coronaviral papain-like protease at the structural and biochemical levels are poorly understood. Therefore, the activity of PLPs from SARS-CoV, MERS-CoV and mouse hepatitis virus (MHV) was evaluated against seven ISG15s originating from an assortment of animal species susceptible, and not, to certain coronavirus infections. Excitingly, our kinetic, thermodynamic and structural analysis revealed an array of different preferences among PLPs. Included in these studies is the first insight into a coronoavirus PLP's interface with ISG15 via SARS-CoV PLP in complex with the principle binding domain of human and mouse ISG15s. The first X-ray structure of the full-length mouse ISG15 protein is also reported and highlights a unique, twisted-hinge region of ISG15 that is not conserved in human ISG15 suggesting a potential role in differential recognition. Taken together, this new information provides a structural and biochemical understanding of the distinct specificities amongst coronavirus PLPs observed and addresses a critical gap of how PLPs can interact with ISG15s from a wide variety of species. Structural insights into the interaction of coronavirus papain-like proteases and interferon-stimulated gene product 15 from different species.,Daczkowski CM, Dzimianski JV, Clasman JR, Goodwin O, Mesecar AD, Pegan SD J Mol Biol. 2017 Apr 21. pii: S0022-2836(17)30187-0. doi:, 10.1016/j.jmb.2017.04.011. PMID:28438633[9] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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