| IED ID | IndEnz0002001422 |
| Enzyme Type ID | protease001422 |
| Protein Name |
Genome polyprotein Cleaved into: Leader protease Lpro EC 3.4.22.46 ; Capsid protein VP0 VP4-VP2 ; Capsid protein VP4 P1A Virion protein 4 ; Capsid protein VP2 P1B Virion protein 2 ; Capsid protein VP3 P1C Virion protein 3 ; Capsid protein VP1 P1D Virion protein 1 ; Protein 2A P2A P52 ; Protein 2B P2B ; Protein 2C P2C EC 3.6.1.15 ; Protein 3A P3A ; Protein 3B-1 P3B-1 Genome-linked protein VPg1 ; Protein 3B-2 P3B-2 Genome-linked protein VPg2 ; Protein 3B-3 P3B-3 Genome-linked protein VPg3 ; Protease 3C EC 3.4.22.28 Picornain 3C P3C Protease P20B ; RNA-directed RNA polymerase 3D-POL P3D-POL EC 2.7.7.48 P56A |
| Gene Name | |
| Organism | Foot-and-mouth disease virus (isolate -/Azerbaijan/A22-550/1965 serotype A) (FMDV) |
| Taxonomic Lineage | Viruses Riboviria Orthornavirae Pisuviricota Pisoniviricetes Picornavirales Picornaviridae Aphthovirus Foot-and-mouth disease virus Foot-and-mouth disease virus - type A Foot-and-mouth disease virus (isolate -/Azerbaijan/A22-550/1965 serotype A) (FMDV) |
| Enzyme Sequence | MNTTDCFIALLYALREIKAFLLSRTQGKMELTLYNGEKKTFYSRPNNHDNCWLNTILQLFRYVDEPFFDWVYDSPENLTCEAIRQLEEITGLELHEGGPPALVIWNIKHLLHTGIGTASRPSEVCMVDGTDMCLADFHAGIFLKGQEHAVFACVTSDGWYAIDDEDFYPWTPDPSDVLVFVPYDQEPLNGEWKAKVQKRLKGAGQSSPATGSQNQSGNTGSIINNYYMQQYQNSMDTQLGDNAISGGSNEGSTDTTSTHTTNTQNNDWFSKLASSAFSGLFGALLADKKTEETTLLEDRILTTRNGHTTSTTQSSVGVTYGYSTQEDHVSGPNTSGLETRVVQAERFFKKYLFDWTPDKAFGHLEKLELPTDHKGVYGHLVDSFAYMRNGWDVEVSAVGNQFNGGCLLVAMVPEWKELTPREKYQLTLFPHQFISPRTNMTAHIVVPYLGVNRYDQYKKHKPWTLVVMVVSPLTTNTVSAGQIKVYANIAPTHVHVAGELPSKEGIVPVACSDGYGGLVTTDPKTADPVYGMVYNPPRTNYPGRFTNLLDVAEACPTFLCFDDGKPYVVTRTDEQRLLAKFDLSLAAKHMSNTYLSGIAQYYAQYSGTINLHFMFTGSTDSKARYMVAYVPPGVETPPDTPEKAAHCIHAEWDTGLNSKFTFSIPYVSAADYAYTASDVAETTNVQGWVCIYQITHGKAEQDTLVVSVSAGKDFELRLPIDPRSQTTSTGESADPVTTTVENYGGETQVQRRQHTDVTFIMDRFVKIQNLNPIHVIDLMQTHQHGLVGALLRAATYYFSDLEIVVRHDGNLTWVPNGAPEAALSNMGNPTAYPKAPFTRLALPYTAPHRVLATVYNGTGKYSAGGMGRRGDLEPLAARVAAQLPTSFNFGAIQATTIHELLVRMKRAELYCPRPLLAVEVSSQDRHKQKIIAPAKQLLNFDLLKLAGDVESNPGPFFFSDVRSNFSKLVETINQMQEDMSTKHGPDFNRLVSAFEELATGVKAIRTGLDEAKPWYKLIKLLSRLSCMAAVAARSKDPVLVAIMLADTGLEILDSTFVVKKISDSLSSLFHVPAPVFSFGAPILLAGLVKVASSFFRSTPEDLERAEKQLKARDINDIFAILKNGEWLVKLILAIRDWIKAWIASEEKFVTMTDLVPGILEKQRDLNDPSKYKEAKEWLDSARQACLKNGNVHIANLCKVVTPAPSKSRPEPVVVCLRGKSGQGKSFLANVLAQAISTHFTGRIDSVWYCPPDPDHFDGYNQQTVVVMDDLGQNPDGKDFKYFAQMVSTTGFIPPMASLEDKGKPFNSKVIITTTNLYSGFTPRTMVCPDALNRRFHFDIDVSAKDGYKVNNKLDITKALEDTHTNPVAMFKYDCALLNGMAVEMKRMQQDMFKPQPPLQNVYQLVQEVIERVELHEKVSSHQIFKQISIPSQKSVLYFLIEKGQHEAAIEFFEGLVHDSIKEELRPLIQQTSFVKRAFKRLKENFEIVALCLTLLANIVIMIRETRKRQQMVDDAVNEYIEKANITTDDKTLDEAEKNPLETSGVSIVGFRERTLPGHRASDDVNSEPARPVEEQPQAEGPYTGPLERQKPLKVKAKLPQQEGPYAGPMERQKPLKVKVKAPVVKEGPYEGPVKKPVALKVKAKNLIVTESGAPPTDLQKMVMGNTKPVELILDGKTVAICCATGVFGTAYLVPRHLFAEKYDKIMLDGRAMTDSDYRVFEFEIKVKGQDMLSDAALMVLHRGNRVRDITKHFRDTARMKKGTPVVGVINNADVGRLIFSGEALTYKDIVVCMDGDTMPGLFAYKAATKAGYCGGAVLAKDGADTFIVGTHSAGGNGVGYCSCVSRSMLLKMKAHIDPEPHHEGLIVDTRDVEERVHVMRKTKLAPTVAHGVFNPEFGPAALSNKDPRLNEGVVLDEVIFSKHKGDTKMTEEDKALFRRCAADYASRLHNVLGTANAPLSIYEAIKGVDGLDAMEPDTAPGLPWALQGKRRGTLIDFENGTVGPEVASALELMEKRQYKFTCQTFLKDEVRPMEKVRAGKTRIVDVLPVEHILYTRMMIGRFCAQMHSNNGPQIGSAVGCNPDVDWQRFGTHFAQYKNVWDVDYSAFDANHCSDAMNIMFEEVFRTEFGFHPNAEWILKTLVNTEHAYENKRITVEGGMPSGCSATSIINTILNNIYVLYALRRHYEGVELDTYTMISYGDDIVVASDYDLDFEALKPHFKSLGQTITPADKSDKGFVLGQSITDVTFLKRHFRMDYGTGFYKPVMASKTLEAILSFARRGTIQEKLISVAGLAVHSGPDEYRRLFEPFQGLFEIPSYRSLYLRWVNAVCGDAQSL |
| Enzyme Length | 2336 |
| Uniprot Accession Number | P49303 |
| Absorption | |
| Active Site | ACT_SITE 51; /note=For leader protease activity; /evidence=ECO:0000250; ACT_SITE 148; /note=For leader protease activity; /evidence=ECO:0000250; ACT_SITE 163; /note=For leader protease activity; /evidence=ECO:0000250; ACT_SITE 1696; /note=For protease 3C activity; Proton donor/acceptor; /evidence=ECO:0000255|PROSITE-ProRule:PRU01222; ACT_SITE 1734; /note=For protease 3C activity; /evidence=ECO:0000255|PROSITE-ProRule:PRU01222; ACT_SITE 1813; /note=For protease 3C activity; /evidence=ECO:0000255|PROSITE-ProRule:PRU01222; ACT_SITE 2201; /note=For RdRp activity; /evidence=ECO:0000250|UniProtKB:P12296 |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=Autocatalytically cleaves itself from the polyprotein of the foot-and-mouth disease virus by hydrolysis of a Lys-|-Gly bond, but then cleaves host cell initiation factor eIF-4G at bonds -Gly-|-Arg- and -Lys-|-Arg-.; EC=3.4.22.46; CATALYTIC ACTIVITY: Reaction=a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-diphosphate + H(+) + phosphate; Xref=Rhea:RHEA:23680, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474, ChEBI:CHEBI:57930, ChEBI:CHEBI:61557; EC=3.6.1.15; CATALYTIC ACTIVITY: Reaction=a ribonucleoside 5'-triphosphate + RNA(n) = diphosphate + RNA(n+1); Xref=Rhea:RHEA:21248, Rhea:RHEA-COMP:14527, Rhea:RHEA-COMP:17342, ChEBI:CHEBI:33019, ChEBI:CHEBI:61557, ChEBI:CHEBI:140395; EC=2.7.7.48; Evidence={ECO:0000255|PROSITE-ProRule:PRU00539}; CATALYTIC ACTIVITY: Reaction=Selective cleavage of Gln-|-Gly bond in the poliovirus polyprotein. In other picornavirus reactions Glu may be substituted for Gln, and Ser or Thr for Gly.; EC=3.4.22.28; Evidence={ECO:0000255|PROSITE-ProRule:PRU01222}; |
| DNA Binding | |
| EC Number | 3.4.22.46; 3.6.1.15; 3.4.22.28; 2.7.7.48 |
| Enzyme Function | FUNCTION: [Leader protease]: Autocatalytically cleaves itself from the polyprotein at the L/VP0 junction. Cleaves also the host translation initiation factors EIF4G1 and EIF4G3, in order to shutoff the capped cellular mRNA transcription. Plays a role in counteracting host innate antiviral response using diverse mechanisms. Possesses a deubiquitinase activity acting on both 'Lys'-48 and 'Lys'-63-linked polyubiquitin chains. In turn, inhibits the ubiquitination and subsequent activation of key signaling molecules of type I IFN response such as host DDX58, TBK1, TRAF3 and TRAF6. Inhibits host NF-kappa-B activity by inducing a decrease in RELA mRNA levels. Cleaves a peptide bond in the C-terminus of host ISG15, resulting in the damaging of this mofidier that can no longer be attached to target proteins. Cleaves also host G3BP1 and G3BP2 in order to inhibit cytoplasmic stress granules assembly. {ECO:0000250|UniProtKB:P03305, ECO:0000250|UniProtKB:P03308}.; FUNCTION: [Leader protease]: Autocatalytically cleaves itself from the polyprotein at the L/VP0 junction. Cleaves also the host translation initiation factors EIF4G1 and EIF4G3, in order to shutoff the capped cellular mRNA transcription. Plays a role in counteracting host innate antiviral response using diverse mechanisms. Possesses a deubiquitinase activity acting on both 'Lys'-48 and 'Lys'-63-linked polyubiquitin chains. In turn, inhibits the ubiquitination and subsequent activation of key signaling molecules of type I IFN response such as host DDX58, TBK1, TRAF3 and TRAF6. Inhibits host NF-kappa-B activity by inducing a decrease in RELA mRNA levels. Cleaves a peptide bond in the C-terminus of host ISG15, resulting in the damaging of this mofidier that can no longer be attached to target proteins. {ECO:0000250|UniProtKB:P03305}.; FUNCTION: Capsid protein VP4: Lies on the inner surface of the capsid shell. After binding to the host receptor, the capsid undergoes conformational changes. Capsid protein VP4 is released, capsid protein VP1 N-terminus is externalized, and together, they shape a pore in the host membrane through which the viral genome is translocated into the host cell cytoplasm. After genome has been released, the channel shrinks. {ECO:0000250|UniProtKB:P03300}.; FUNCTION: Capsid protein VP2: Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP1 and VP3. The capsid is composed of 60 copies of each capsid protein organized in the form of twelve pentamers and encloses the viral positive strand RNA genome. {ECO:0000250|UniProtKB:P03305}.; FUNCTION: Capsid protein V1: Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP2 and VP3. The capsid is composed of 60 copies of each capsid protein organized in the form of twelve pentamers and encloses the viral positive strand RNA genome. Mediates cell entry by attachment to an integrin receptor, usually host ITGAV/ITGB6, via a conserved arginine-glycine-aspartic acid (R-G-D) motif. {ECO:0000250|UniProtKB:P03305}.; FUNCTION: Capsid protein V3: Forms an icosahedral capsid of pseudo T=3 symmetry with capsid proteins VP0 and VP3. The capsid is composed of 60 copies of each capsid protein organized in the form of twelve pentamers and encloses the viral positive strand RNA genome. {ECO:0000250|UniProtKB:P03305}.; FUNCTION: [Protein 2A]: Mediates self-processing of the polyprotein by a translational effect termed 'ribosome skipping'. Mechanistically, 2A-mediated cleavage occurs between the C-terminal glycine and the proline of the downstream protein 2B. In the case of foot-and-mouth disease virus, the 2A oligopeptide is post-translationally 'trimmed' from the C-terminus of the upstream protein 1D by 3C proteinase. {ECO:0000250|UniProtKB:P03305}.; FUNCTION: [Protein 2B]: Plays an essential role in the virus replication cycle by acting as a viroporin. Creates a pore in the host reticulum endoplasmic and as a consequence releases Ca2+ in the cytoplasm of infected cell. In turn, high levels of cytoplasmic calcium may trigger membrane trafficking and transport of viral ER-associated proteins to viroplasms, sites of viral genome replication. {ECO:0000250|UniProtKB:P03305}.; FUNCTION: [Protein 2C]: Associates with and induces structural rearrangements of intracellular membranes. Triggers host autophagy by interacting with host BECN1 and thereby promotes viral replication. Participates in viral replication and interacts with host DHX9. Displays RNA-binding, nucleotide binding and NTPase activities. May play a role in virion morphogenesis and viral RNA encapsidation by interacting with the capsid protein VP3. {ECO:0000250|UniProtKB:P03305}.; FUNCTION: [Protein 3A]: Plays important roles in virus replication, virulence and host range. {ECO:0000250|UniProtKB:P03305}.; FUNCTION: [Protein 3B-1]: Covalently linked to the 5'-end of both the positive-strand and negative-strand genomic RNAs. Acts as a genome-linked replication primer. {ECO:0000250|UniProtKB:P03305}.; FUNCTION: [Protein 3B-2]: Covalently linked to the 5'-end of both the positive-strand and negative-strand genomic RNAs. Acts as a genome-linked replication primer. {ECO:0000250|UniProtKB:P03305}.; FUNCTION: [Protein 3B-3]: Covalently linked to the 5'-end of both the positive-strand and negative-strand genomic RNAs. Acts as a genome-linked replication primer. {ECO:0000250|UniProtKB:P03305}.; FUNCTION: [Protease 3C]: Cysteine protease that generates mature viral proteins from the precursor polyprotein. In addition to its proteolytic activity, binds to viral RNA and thus influences viral genome replication. RNA and substrate bind cooperatively to the protease. {ECO:0000250|UniProtKB:P03305}.; FUNCTION: RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals. Covalently attaches UMP to a tyrosine of VPg, which is used to prime RNA synthesis. The positive stranded RNA genome is first replicated at virus induced membranous vesicles, creating a dsRNA genomic replication form. This dsRNA is then used as template to synthesize positive stranded RNA genomes. ss(+)RNA genomes are either translated, replicated or encapsidated. {ECO:0000250|UniProtKB:P03305}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 1218..1225; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00551 |
| Features | Active site (7); Alternative sequence (1); Chain (16); Compositional bias (1); Disulfide bond (1); Domain (4); Helix (2); Intramembrane (1); Lipidation (1); Modified residue (3); Motif (1); Natural variant (4); Nucleotide binding (1); Region (3); Site (13); Topological domain (2) |
| Keywords | 3D-structure;ATP-binding;Alternative initiation;Capsid protein;Clathrin-mediated endocytosis of virus by host;Covalent protein-RNA linkage;Disulfide bond;Helicase;Host cytoplasm;Host cytoplasmic vesicle;Host membrane;Host-virus interaction;Hydrolase;Ion channel;Ion transport;Lipoprotein;Membrane;Modulation of host chromatin by virus;Myristate;Nucleotide-binding;Nucleotidyltransferase;Phosphoprotein;Protease;RNA-binding;RNA-directed RNA polymerase;T=pseudo3 icosahedral capsid protein;Thiol protease;Transferase;Translation regulation;Transport;Viral RNA replication;Viral attachment to host cell;Viral ion channel;Viral penetration into host cytoplasm;Virion;Virus endocytosis by host;Virus entry into host cell |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: [Capsid protein VP2]: Virion. Host cytoplasm {ECO:0000305}.; SUBCELLULAR LOCATION: [Capsid protein VP3]: Virion. Host cytoplasm {ECO:0000305}.; SUBCELLULAR LOCATION: [Capsid protein VP1]: Virion. Host cytoplasm {ECO:0000305}.; SUBCELLULAR LOCATION: [Protein 2B]: Host cytoplasmic vesicle membrane {ECO:0000305}; Peripheral membrane protein {ECO:0000305}; Cytoplasmic side {ECO:0000305}. Note=Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum (By similarity). {ECO:0000250}.; SUBCELLULAR LOCATION: [Protein 2C]: Host cytoplasmic vesicle membrane {ECO:0000305}; Peripheral membrane protein {ECO:0000305}; Cytoplasmic side {ECO:0000305}. Note=Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum (By similarity). {ECO:0000250}.; SUBCELLULAR LOCATION: [Protein 3A]: Host cytoplasmic vesicle membrane {ECO:0000305}; Peripheral membrane protein {ECO:0000305}; Cytoplasmic side {ECO:0000305}. Note=Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum (By similarity). {ECO:0000250}.; SUBCELLULAR LOCATION: [Protein 3B-1]: Virion {ECO:0000305}.; SUBCELLULAR LOCATION: [Protein 3B-2]: Virion {ECO:0000305}.; SUBCELLULAR LOCATION: [Protein 3B-3]: Virion {ECO:0000305}.; SUBCELLULAR LOCATION: [Protease 3C]: Host cytoplasm {ECO:0000305}.; SUBCELLULAR LOCATION: [RNA-directed RNA polymerase 3D-POL]: Host cytoplasmic vesicle membrane {ECO:0000305}; Peripheral membrane protein {ECO:0000305}; Cytoplasmic side {ECO:0000305}. Note=Probably localizes to the surface of intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. These vesicles are derived from the endoplasmic reticulum (By similarity). {ECO:0000250}. |
| Modified Residue | MOD_RES 1582; /note=O-(5'-phospho-RNA)-tyrosine; /evidence=ECO:0000250; MOD_RES 1605; /note=O-(5'-phospho-RNA)-tyrosine; /evidence=ECO:0000250; MOD_RES 1629; /note=O-(5'-phospho-RNA)-tyrosine; /evidence=ECO:0000250 |
| Post Translational Modification | PTM: Specific enzymatic cleavages in vivo by the viral proteases yield a variety of precursors and mature proteins. Polyprotein processing intermediates such as VP0 which is a VP4-VP2 precursor are produced. During virion maturation, non-infectious particles are rendered infectious following cleavage of VP0. This maturation cleavage is followed by a conformational change of the particle. The polyprotein seems to be cotranslationally cleaved at the 2A/2B junction by a ribosomal skip from one codon to the next without formation of a peptide bond. This process would release the L-P1-2A peptide from the translational complex (By similarity). {ECO:0000250}.; PTM: Myristoylation of VP4 is required during RNA encapsidation and formation of the mature virus particle. {ECO:0000250}.; PTM: Protein 3B-1, 3B-2 and 3B-3 are uridylylated by the polymerase and are covalently linked to the 5'-end of genomic RNA. These uridylylated forms act as a nucleotide-peptide primer for the polymerase (By similarity). {ECO:0000250}. |
| Signal Peptide | |
| Structure 3D | Electron microscopy (1); X-ray crystallography (2) |
| Cross Reference PDB | 1FMD; 6A6H; 7D3R; |
| Mapped Pubmed ID | 31760318; 33909694; |
| Motif | MOTIF 869..871; /note=Cell attachment site |
| Gene Encoded By | |
| Mass | 259,985 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:23680; RHEA:21248 |
| Cross Reference Brenda |