| Structural highlights
Function
[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.[1] [2] [3] [4] 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.[5] [6] [7] [8] Protein VP0: VP0 precursor is a component of immature procapsids (By similarity).[9] [10] [11] [12] Protein 2B: Affects membrane integrity and cause an increase in membrane permeability (By similarity).[13] [14] [15] [16] Protein 2C: Associates with and induces structural rearrangements of intracellular membranes. It displays RNA-binding, nucleotide binding and NTPase activities (By similarity).[17] [18] [19] [20] Protein 3A, via its hydrophobic domain, serves as membrane anchor (By similarity).[21] [22] [23] [24] 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).[25] [26] [27] [28] 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).[29] [30] [31] [32] RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals (By similarity).[33] [34] [35] [36] [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.[37] [38] [39] [40] [41] [42] 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).[43] [44] [45] [46] [47] [48]
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[49]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Medina M, Domingo E, Brangwyn JK, Belsham GJ. The two species of the foot-and-mouth disease virus leader protein, expressed individually, exhibit the same activities. Virology. 1993 May;194(1):355-9. PMID:8386879 doi:http://dx.doi.org/S0042-6822(83)71267-5
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Gradi A, Foeger N, Strong R, Svitkin YV, Sonenberg N, Skern T, Belsham GJ. Cleavage of eukaryotic translation initiation factor 4GII within foot-and-mouth disease virus-infected cells: identification of the L-protease cleavage site in vitro. J Virol. 2004 Apr;78(7):3271-8. PMID:15016848
- ↑ O'Donnell V, Larocco M, Baxt B. Heparan sulfate-binding foot-and-mouth disease virus enters cells via caveola-mediated endocytosis. J Virol. 2008 Sep;82(18):9075-85. doi: 10.1128/JVI.00732-08. Epub 2008 Jul 9. PMID:18614639 doi:http://dx.doi.org/10.1128/JVI.00732-08
- ↑ Medina M, Domingo E, Brangwyn JK, Belsham GJ. The two species of the foot-and-mouth disease virus leader protein, expressed individually, exhibit the same activities. Virology. 1993 May;194(1):355-9. PMID:8386879 doi:http://dx.doi.org/S0042-6822(83)71267-5
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Gradi A, Foeger N, Strong R, Svitkin YV, Sonenberg N, Skern T, Belsham GJ. Cleavage of eukaryotic translation initiation factor 4GII within foot-and-mouth disease virus-infected cells: identification of the L-protease cleavage site in vitro. J Virol. 2004 Apr;78(7):3271-8. PMID:15016848
- ↑ O'Donnell V, Larocco M, Baxt B. Heparan sulfate-binding foot-and-mouth disease virus enters cells via caveola-mediated endocytosis. J Virol. 2008 Sep;82(18):9075-85. doi: 10.1128/JVI.00732-08. Epub 2008 Jul 9. PMID:18614639 doi:http://dx.doi.org/10.1128/JVI.00732-08
- ↑ Medina M, Domingo E, Brangwyn JK, Belsham GJ. The two species of the foot-and-mouth disease virus leader protein, expressed individually, exhibit the same activities. Virology. 1993 May;194(1):355-9. PMID:8386879 doi:http://dx.doi.org/S0042-6822(83)71267-5
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Gradi A, Foeger N, Strong R, Svitkin YV, Sonenberg N, Skern T, Belsham GJ. Cleavage of eukaryotic translation initiation factor 4GII within foot-and-mouth disease virus-infected cells: identification of the L-protease cleavage site in vitro. J Virol. 2004 Apr;78(7):3271-8. PMID:15016848
- ↑ O'Donnell V, Larocco M, Baxt B. Heparan sulfate-binding foot-and-mouth disease virus enters cells via caveola-mediated endocytosis. J Virol. 2008 Sep;82(18):9075-85. doi: 10.1128/JVI.00732-08. Epub 2008 Jul 9. PMID:18614639 doi:http://dx.doi.org/10.1128/JVI.00732-08
- ↑ Medina M, Domingo E, Brangwyn JK, Belsham GJ. The two species of the foot-and-mouth disease virus leader protein, expressed individually, exhibit the same activities. Virology. 1993 May;194(1):355-9. PMID:8386879 doi:http://dx.doi.org/S0042-6822(83)71267-5
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Gradi A, Foeger N, Strong R, Svitkin YV, Sonenberg N, Skern T, Belsham GJ. Cleavage of eukaryotic translation initiation factor 4GII within foot-and-mouth disease virus-infected cells: identification of the L-protease cleavage site in vitro. J Virol. 2004 Apr;78(7):3271-8. PMID:15016848
- ↑ O'Donnell V, Larocco M, Baxt B. Heparan sulfate-binding foot-and-mouth disease virus enters cells via caveola-mediated endocytosis. J Virol. 2008 Sep;82(18):9075-85. doi: 10.1128/JVI.00732-08. Epub 2008 Jul 9. PMID:18614639 doi:http://dx.doi.org/10.1128/JVI.00732-08
- ↑ Medina M, Domingo E, Brangwyn JK, Belsham GJ. The two species of the foot-and-mouth disease virus leader protein, expressed individually, exhibit the same activities. Virology. 1993 May;194(1):355-9. PMID:8386879 doi:http://dx.doi.org/S0042-6822(83)71267-5
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Gradi A, Foeger N, Strong R, Svitkin YV, Sonenberg N, Skern T, Belsham GJ. Cleavage of eukaryotic translation initiation factor 4GII within foot-and-mouth disease virus-infected cells: identification of the L-protease cleavage site in vitro. J Virol. 2004 Apr;78(7):3271-8. PMID:15016848
- ↑ O'Donnell V, Larocco M, Baxt B. Heparan sulfate-binding foot-and-mouth disease virus enters cells via caveola-mediated endocytosis. J Virol. 2008 Sep;82(18):9075-85. doi: 10.1128/JVI.00732-08. Epub 2008 Jul 9. PMID:18614639 doi:http://dx.doi.org/10.1128/JVI.00732-08
- ↑ Medina M, Domingo E, Brangwyn JK, Belsham GJ. The two species of the foot-and-mouth disease virus leader protein, expressed individually, exhibit the same activities. Virology. 1993 May;194(1):355-9. PMID:8386879 doi:http://dx.doi.org/S0042-6822(83)71267-5
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Gradi A, Foeger N, Strong R, Svitkin YV, Sonenberg N, Skern T, Belsham GJ. Cleavage of eukaryotic translation initiation factor 4GII within foot-and-mouth disease virus-infected cells: identification of the L-protease cleavage site in vitro. J Virol. 2004 Apr;78(7):3271-8. PMID:15016848
- ↑ O'Donnell V, Larocco M, Baxt B. Heparan sulfate-binding foot-and-mouth disease virus enters cells via caveola-mediated endocytosis. J Virol. 2008 Sep;82(18):9075-85. doi: 10.1128/JVI.00732-08. Epub 2008 Jul 9. PMID:18614639 doi:http://dx.doi.org/10.1128/JVI.00732-08
- ↑ Medina M, Domingo E, Brangwyn JK, Belsham GJ. The two species of the foot-and-mouth disease virus leader protein, expressed individually, exhibit the same activities. Virology. 1993 May;194(1):355-9. PMID:8386879 doi:http://dx.doi.org/S0042-6822(83)71267-5
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Gradi A, Foeger N, Strong R, Svitkin YV, Sonenberg N, Skern T, Belsham GJ. Cleavage of eukaryotic translation initiation factor 4GII within foot-and-mouth disease virus-infected cells: identification of the L-protease cleavage site in vitro. J Virol. 2004 Apr;78(7):3271-8. PMID:15016848
- ↑ O'Donnell V, Larocco M, Baxt B. Heparan sulfate-binding foot-and-mouth disease virus enters cells via caveola-mediated endocytosis. J Virol. 2008 Sep;82(18):9075-85. doi: 10.1128/JVI.00732-08. Epub 2008 Jul 9. PMID:18614639 doi:http://dx.doi.org/10.1128/JVI.00732-08
- ↑ Medina M, Domingo E, Brangwyn JK, Belsham GJ. The two species of the foot-and-mouth disease virus leader protein, expressed individually, exhibit the same activities. Virology. 1993 May;194(1):355-9. PMID:8386879 doi:http://dx.doi.org/S0042-6822(83)71267-5
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Gradi A, Foeger N, Strong R, Svitkin YV, Sonenberg N, Skern T, Belsham GJ. Cleavage of eukaryotic translation initiation factor 4GII within foot-and-mouth disease virus-infected cells: identification of the L-protease cleavage site in vitro. J Virol. 2004 Apr;78(7):3271-8. PMID:15016848
- ↑ O'Donnell V, Larocco M, Baxt B. Heparan sulfate-binding foot-and-mouth disease virus enters cells via caveola-mediated endocytosis. J Virol. 2008 Sep;82(18):9075-85. doi: 10.1128/JVI.00732-08. Epub 2008 Jul 9. PMID:18614639 doi:http://dx.doi.org/10.1128/JVI.00732-08
- ↑ Medina M, Domingo E, Brangwyn JK, Belsham GJ. The two species of the foot-and-mouth disease virus leader protein, expressed individually, exhibit the same activities. Virology. 1993 May;194(1):355-9. PMID:8386879 doi:http://dx.doi.org/S0042-6822(83)71267-5
- ↑ Glaser W, Skern T. Extremely efficient cleavage of eIF4G by picornaviral proteinases L and 2A in vitro. FEBS Lett. 2000 Sep 1;480(2-3):151-5. PMID:11034318
- ↑ Gradi A, Foeger N, Strong R, Svitkin YV, Sonenberg N, Skern T, Belsham GJ. Cleavage of eukaryotic translation initiation factor 4GII within foot-and-mouth disease virus-infected cells: identification of the L-protease cleavage site in vitro. J Virol. 2004 Apr;78(7):3271-8. PMID:15016848
- ↑ O'Donnell V, Larocco M, Baxt B. Heparan sulfate-binding foot-and-mouth disease virus enters cells via caveola-mediated endocytosis. J Virol. 2008 Sep;82(18):9075-85. doi: 10.1128/JVI.00732-08. Epub 2008 Jul 9. PMID:18614639 doi:http://dx.doi.org/10.1128/JVI.00732-08
- ↑ Loeb KR, Haas AL. The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. J Biol Chem. 1992 Apr 15;267(11):7806-13. PMID:1373138
- ↑ Loeb KR, Haas AL. Conjugates of ubiquitin cross-reactive protein distribute in a cytoskeletal pattern. Mol Cell Biol. 1994 Dec;14(12):8408-19. PMID:7526157
- ↑ Narasimhan J, Potter JL, Haas AL. Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct from that of ubiquitin. J Biol Chem. 1996 Jan 5;271(1):324-30. PMID:8550581
- ↑ Knight E Jr, Cordova B. IFN-induced 15-kDa protein is released from human lymphocytes and monocytes. J Immunol. 1991 Apr 1;146(7):2280-4. PMID:2005397
- ↑ Lenschow DJ, Giannakopoulos NV, Gunn LJ, Johnston C, O'Guin AK, Schmidt RE, Levine B, Virgin HW 4th. Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. J Virol. 2005 Nov;79(22):13974-83. PMID:16254333 doi:79/22/13974
- ↑ Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM. Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10200-5. Epub 2005 Jul 11. PMID:16009940 doi:0504754102
- ↑ Loeb KR, Haas AL. The interferon-inducible 15-kDa ubiquitin homolog conjugates to intracellular proteins. J Biol Chem. 1992 Apr 15;267(11):7806-13. PMID:1373138
- ↑ Loeb KR, Haas AL. Conjugates of ubiquitin cross-reactive protein distribute in a cytoskeletal pattern. Mol Cell Biol. 1994 Dec;14(12):8408-19. PMID:7526157
- ↑ Narasimhan J, Potter JL, Haas AL. Conjugation of the 15-kDa interferon-induced ubiquitin homolog is distinct from that of ubiquitin. J Biol Chem. 1996 Jan 5;271(1):324-30. PMID:8550581
- ↑ Knight E Jr, Cordova B. IFN-induced 15-kDa protein is released from human lymphocytes and monocytes. J Immunol. 1991 Apr 1;146(7):2280-4. PMID:2005397
- ↑ Lenschow DJ, Giannakopoulos NV, Gunn LJ, Johnston C, O'Guin AK, Schmidt RE, Levine B, Virgin HW 4th. Identification of interferon-stimulated gene 15 as an antiviral molecule during Sindbis virus infection in vivo. J Virol. 2005 Nov;79(22):13974-83. PMID:16254333 doi:79/22/13974
- ↑ Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM. Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10200-5. Epub 2005 Jul 11. PMID:16009940 doi:0504754102
- ↑ 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
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