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==FMDV Leader protease bound to substrate ISG15==
==FMDV Leader protease bound to substrate ISG15==
<StructureSection load='6ffa' size='340' side='right' caption='[[6ffa]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
<StructureSection load='6ffa' size='340' side='right'caption='[[6ffa]], [[Resolution|resolution]] 1.50&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6ffa]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FFA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6FFA FirstGlance]. <br>
<table><tr><td colspan='2'>[[6ffa]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Foot-and-mouth_disease_virus Foot-and-mouth disease virus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6FFA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6FFA FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.5&#8491;</td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=AYE:PROP-2-EN-1-AMINE'>AYE</scene></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AYE:PROP-2-EN-1-AMINE'>AYE</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ffa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ffa OCA], [http://pdbe.org/6ffa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ffa RCSB], [http://www.ebi.ac.uk/pdbsum/6ffa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ffa ProSAT]</span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6ffa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ffa OCA], [https://pdbe.org/6ffa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ffa RCSB], [https://www.ebi.ac.uk/pdbsum/6ffa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ffa ProSAT]</span></td></tr>
</table>
</table>
== Function ==
<div style="background-color:#fffaf0;">
[[http://www.uniprot.org/uniprot/POLG_FMDVO POLG_FMDVO]] The leader protease autocatalytically cleaves itself from the polyprotein at the L/VP0 junction. It also cleaves the host translation initiation factor EIF4G1 and EIF4G3, in order to shut down the capped cellular mRNA transcription.<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>  Capsid proteins VP1, VP2, VP3 and VP4 form a closed capsid enclosing the viral positive strand RNA genome. VP4 lies on the inner surface of the protein shell formed by VP1, VP2 and VP3. All the three latter proteins contain a beta-sheet structure called beta-barrel jelly roll. Together they form an icosahedral capsid (T=3) composed of 60 copies of each VP1, VP2, and VP3, with a diameter of approximately 300 Angstroms. VP1 is situated at the 12 fivefold axes, whereas VP2 and VP3 are located at the quasi-sixfold axes. The capsid interacts with host heparan sulfate and various integrins (alphavbeta6, alphavbeta1, alphavbeta3, alpha5beta1, alphavbeta8) to provide virion attachment to target Attachment via host integrins induces virion internalization predominantly through clathrin-mediated endocytosis. In strains adapted to cell culture, attachment to heparan sulfate can also be used and induces virion internalization through clathrin- and caveolin-independent endocytosis.<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>  Protein VP0: VP0 precursor is a component of immature procapsids (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>  Protein 2B: Affects membrane integrity and cause an increase in membrane permeability (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>  Protein 2C: Associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>  Protein 3A, via its hydrophobic domain, serves as membrane anchor (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>  Protein 3B-1, 3B-2 and 3B-3 are covalently linked to the 5'-end of both the positive-strand and negative-strand genomic RNAs. They acts as a genome-linked replication primer (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>  Protease 3C: cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, it binds to viral RNA, and thus influences viral genome replication. RNA and substrate bind cooperatively to the protease (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>  RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).<ref>PMID:8386879</ref> <ref>PMID:11034318</ref> <ref>PMID:15016848</ref> <ref>PMID:18614639</ref>  [[http://www.uniprot.org/uniprot/ISG15_HUMAN 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.<ref>PMID:1373138</ref> <ref>PMID:7526157</ref> <ref>PMID:8550581</ref> <ref>PMID:2005397</ref> <ref>PMID:16254333</ref> <ref>PMID:16009940</ref>  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).<ref>PMID:1373138</ref> <ref>PMID:7526157</ref> <ref>PMID:8550581</ref> <ref>PMID:2005397</ref> <ref>PMID:16254333</ref> <ref>PMID:16009940</ref>
== Publication Abstract from PubMed ==
In response to viral infection, cells mount a potent inflammatory response that relies on ISG15 and ubiquitin posttranslational modifications. Many viruses use deubiquitinases and deISGylases that reverse these modifications and antagonize host signaling processes. We here reveal that the leader protease, Lb(pro), from foot-and-mouth disease virus (FMDV) targets ISG15 and to a lesser extent, ubiquitin in an unprecedented manner. Unlike canonical deISGylases that hydrolyze the isopeptide linkage after the C-terminal GlyGly motif, Lb(pro) cleaves the peptide bond preceding the GlyGly motif. Consequently, the GlyGly dipeptide remains attached to the substrate Lys, and cleaved ISG15 is rendered incompetent for reconjugation. A crystal structure of Lb(pro) bound to an engineered ISG15 suicide probe revealed the molecular basis for ISG15 proteolysis. Importantly, anti-GlyGly antibodies, developed for ubiquitin proteomics, are able to detect Lb(pro) cleavage products during viral infection. This opens avenues for infection detection of FMDV based on an immutable, host-derived epitope.
 
Irreversible inactivation of ISG15 by a viral leader protease enables alternative infection detection strategies.,Swatek KN, Aumayr M, Pruneda JN, Visser LJ, Berryman S, Kueck AF, Geurink PP, Ovaa H, van Kuppeveld FJM, Tuthill TJ, Skern T, Komander D Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):2371-2376. doi:, 10.1073/pnas.1710617115. Epub 2018 Feb 20. PMID:29463763<ref>PMID:29463763</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6ffa" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Komander, D]]
[[Category: Foot-and-mouth disease virus]]
[[Category: Pruneda, J N]]
[[Category: Homo sapiens]]
[[Category: Swatek, K N]]
[[Category: Large Structures]]
[[Category: Deisgylase]]
[[Category: Komander D]]
[[Category: Deubiquitinase]]
[[Category: Pruneda JN]]
[[Category: Hydrolase]]
[[Category: Swatek KN]]
[[Category: Leader protease]]

Latest revision as of 10:57, 17 October 2024

FMDV Leader protease bound to substrate ISG15FMDV Leader protease bound to substrate ISG15

Structural highlights

6ffa is a 2 chain structure with sequence from Foot-and-mouth disease virus and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.5Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

In response to viral infection, cells mount a potent inflammatory response that relies on ISG15 and ubiquitin posttranslational modifications. Many viruses use deubiquitinases and deISGylases that reverse these modifications and antagonize host signaling processes. We here reveal that the leader protease, Lb(pro), from foot-and-mouth disease virus (FMDV) targets ISG15 and to a lesser extent, ubiquitin in an unprecedented manner. Unlike canonical deISGylases that hydrolyze the isopeptide linkage after the C-terminal GlyGly motif, Lb(pro) cleaves the peptide bond preceding the GlyGly motif. Consequently, the GlyGly dipeptide remains attached to the substrate Lys, and cleaved ISG15 is rendered incompetent for reconjugation. A crystal structure of Lb(pro) bound to an engineered ISG15 suicide probe revealed the molecular basis for ISG15 proteolysis. Importantly, anti-GlyGly antibodies, developed for ubiquitin proteomics, are able to detect Lb(pro) cleavage products during viral infection. This opens avenues for infection detection of FMDV based on an immutable, host-derived epitope.

Irreversible inactivation of ISG15 by a viral leader protease enables alternative infection detection strategies.,Swatek KN, Aumayr M, Pruneda JN, Visser LJ, Berryman S, Kueck AF, Geurink PP, Ovaa H, van Kuppeveld FJM, Tuthill TJ, Skern T, Komander D Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):2371-2376. doi:, 10.1073/pnas.1710617115. Epub 2018 Feb 20. PMID:29463763[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ Swatek KN, Aumayr M, Pruneda JN, Visser LJ, Berryman S, Kueck AF, Geurink PP, Ovaa H, van Kuppeveld FJM, Tuthill TJ, Skern T, Komander D. Irreversible inactivation of ISG15 by a viral leader protease enables alternative infection detection strategies. Proc Natl Acad Sci U S A. 2018 Mar 6;115(10):2371-2376. doi:, 10.1073/pnas.1710617115. Epub 2018 Feb 20. PMID:29463763 doi:http://dx.doi.org/10.1073/pnas.1710617115

6ffa, resolution 1.50Å

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