| IED ID | IndEnz0002011244 |
| Enzyme Type ID | protease011244 |
| Protein Name |
Genome polyprotein Cleaved into: 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 ; Protein VP1-2A VPX ; Capsid protein VP1 P1D Virion protein 1 ; Assembly signal 2A pX ; Protein 2BC; Protein 2B P2B ; Protein 2C P2C EC 3.6.1.15 ; Protein 3ABCD P3 ; Protein 3ABC; Protein 3AB; Protein 3A P3A ; Viral protein genome-linked VPg Protein 3B P3B ; Protein 3CD; Protease 3C P3C EC 3.4.22.28 Picornain 3C ; RNA-directed RNA polymerase 3D-POL P3D-POL EC 2.7.7.48 |
| Gene Name | |
| Organism | Human hepatitis A virus genotype IA (isolate H2) (HHAV) (Human hepatitis A virus (isolate Human/China/H2/1982)) |
| Taxonomic Lineage | Viruses Riboviria Orthornavirae Pisuviricota Pisoniviricetes Picornavirales Picornaviridae Hepatovirus Hepatovirus A Human hepatitis A virus Human hepatitis A virus genotype IA (isolate H2) (HHAV) (Human hepatitis A virus (isolate Human/China/H2/1982)) |
| Enzyme Sequence | MNMSKQGIFQTVGSGLDHILSLADIEEEQMIQSVDRTAVTGASYFTSVDQSSVHTAEVGSHQIEPLKTSVDKPGSKKTQGEKFFLIHSADWLTTHALFHEVAKLDVVKLLYNEQFAVQGLLRYHTYARFGIEIQVQINPTPFQQGGLICAMVPGDQSYGSIASLTVYPHGLLNCNINNVVRIKVPFIYTRGAYHFKDPQYPVWELTIRVWSELNIGTGTSAYTSLNVLARFTDLELHGLTPLSTQMMRNEFRVSTTENVVNLSNYEDARAKMSFALDPEDWKSDPSQGGGIKITHFTTWTSIPTLAAQFPFNASDSVGQQIKVIPVDPYFFQMTNTNPDQKCITALASICQMFCFWRGDLVFDFQVFPTKYHSGRLLFCFVPGNELIDVTGITLKQATTAPCAVMDITGVQSTLRFRVPWISDTPYRVNRYTKSAHQKGEYTAIGKLIVYCYNRLTSPSNVASHVRVNVYLSAINLECFAPLYHAMDVTTQVGDDSGGFSTTVSTEQNVPDPQVGITTMRDLKGKANRGKMDVSGVQAPVGAITTIEDPVLAKKVPETFPELKPGESRHTSDHMSIYKFMGRSHFLCTFTFNSNNKEYTFPITLSSTSNPPHGLPSTLRWFFNLFQLYRGPLDLTIIITGATDVDGMAWFTPVGLAVDTPWVEKESALSIDYKTALGAVRFNTRRTGNIQIRLPWYSYLYAVSGALDGLGDKTDSTFGLVSIQIANYNHSDEYLSFSCYLSVTEQSEFYFPRAPLNSNAMLSTESMMSRIAAGDLESSVDDPRSEEDRRFESHIECRKPYKELRLEVGKQRLKYAQEELSNEVLPPPRKMKGLFSQAKISLFYTEEHEIMKFSWRGVTADTRALRRFGFSMAAGRSVWTLEMDAGVLTGRLVRLNDEKWTEMKDDKIVSLIEKFTSNKYWSKVSFPHGMLDLEEIAANSTDFPNMSETDLCFLLHWLNPKKINLADRMLGLSGVQEIKEQGVGLIAECRTFLDSIAGTLKSMMFGFHHSVTVEIINTVLCFVKSGILLYVIQQLNQDEHSHIIGLLRVMNYADIGCSVISCGKVFSKMLETVFNWQMDSRMMELRTQSFSNWLRDICSGITIFKSFKDAIYWLYTKLKDFYEVNYGKKKDILNILKDNQQKIEKAIEEADNFCILQIQDVEKFDQYQKGVDLIQKLRTVHSMAQVDPNLGVHLSPLRDCIARVHQKLKNLGSINQAMVTRCEPVVCYLYGKRGGGKSLTSIALATKICKHYGVEPEKNIYTKPVASDYWDGYSGQLVCIIDDIGQNTTDEDWSDFCQLVSGCPMRLNMASLEEKGRHFSSPFIIATSNWSNPSPKTVYVKEAIDRRLHFKVEVKPASFFKNPHNDMLNVNLAKTNDAIKDMSCVDLIMDGHNISLMDLLSSLVMTVEIRKQNMSEFMELWSQGISDDDNDSAVAEFFQSFPSGEPSNSKLSSFFQSVTNHKWVAVGAAVGILGVLVGGWFVYKHFSRKEEEPIPAEGVYHGVTKPKQVIKLDADPVESQSTLEIAGLVRKNLVQFGVGEKNGCVRWVMNALGVKDDWLLVPSHAYKFEKDYEMMEFYFNRGGTYYSISAGNVVIQSLDVGFQDVVLMKVPTIPKFRDITQHFIKKGDVPRALNRLATLVTTVNGTPMLISEGPLKMEEKATYVHKKNDGTTVDLTVDQAWRGKGEGLPGMCGGALVSSNQSIQNAILGIHVAGGNSILVAKLVTQEMFQNIDKKIESQRIMKVEFTQCSMNVVSKTLFRKSPIHHHIDKTMINFPAVMPFSKAEVDPMAVMLSKYSLPIVEEPEDYKEASIFYQNKIVGKTQLVDDFLDLDMAITGAPGIDAINMDSSPGFPYVQEKLTKRDLIWLDENGLLLGVHPRLAQRILFNTVMMENCSDLDVVFTTCPKDELRPLEKVLESKTRAIDACPLDYTILCRMYWGPAISYFHLNPGFHTGVAIGIDPDRQWDELFKTMIRFGDVGLDLDFSAFDASLSPFMIREAGRIMSELSGTPSHFGTALINTIIYSKHLLYNCCYHVCGSMPSGSPCTALLNSIINNINLYYVFSKIFGKSPVFFCQALRILCYGDDVLIVFSRDVQIDNLDLIGQKIVDEFKKLGMTATSADKNVPQLKPVSELTFLKRSFNLVEDRIRPAISEKTIWSLIAWQRSNAEFEQNLENAQWFAFMHGYEFYQKFYYFVQSCLEKEMIEYRLKSYDWWRMRFYDQCFICDLS |
| Enzyme Length | 2227 |
| Uniprot Accession Number | A3FMB2 |
| Absorption | |
| Active Site | ACT_SITE 1563; /note=For protease 3C activity; /evidence=ECO:0000255|PROSITE-ProRule:PRU01222; ACT_SITE 1603; /note=For protease 3C activity; /evidence=ECO:0000255|PROSITE-ProRule:PRU01222; ACT_SITE 1691; /note=For protease 3C activity; /evidence=ECO:0000255|PROSITE-ProRule:PRU01222 |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | 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:0000250|UniProtKB:P08617, ECO:0000255|PROSITE-ProRule:PRU00539}; 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; Evidence={ECO:0000250|UniProtKB:P08617}; 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 | 3.6.1.15; 3.4.22.28; 2.7.7.48 |
| Enzyme Function | FUNCTION: [Capsid protein VP1]: Capsid proteins VP1, VP2, and VP3 form a closed capsid enclosing the viral positive strand RNA genome. All these 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 naked capsid interacts with the host receptor HAVCR1 to provide virion attachment to and probably entry into the target cell. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Capsid protein VP2]: Capsid proteins VP1, VP2, and VP3 form a closed capsid enclosing the viral positive strand RNA genome. All these 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 naked capsid interacts with the host receptor HAVCR1 to provide virion attachment to and probably entry into the target cell. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Capsid protein VP3]: Capsid proteins VP1, VP2, and VP3 form a closed capsid enclosing the viral positive strand RNA genome. All these 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 naked capsid interacts with the host receptor HAVCR1 to provide virion attachment to and probably entry into the target cell. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Capsid protein VP0]: VP0 precursor is a component of the immature procapsids. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Capsid protein VP4]: Plays a role in the assembly of the 12 pentamers into an icosahedral structure. Has not been detected in mature virions, supposedly owing to its small size. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Protein VP1-2A]: Precursor component of immature procapsids that corresponds to an extended form of the structural protein VP1. After maturation, possibly by the host Cathepsin L, the assembly signal 2A is cleaved to give rise to the mature VP1 protein. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Protein 2B]: Functions as a viroporin. Affects membrane integrity and causes an increase in membrane permeability. Involved in host intracellular membrane rearrangements probably to give rise to the viral factories. Does not disrupt calcium homeostasis or glycoprotein trafficking. Antagonizes the innate immune response of the host by suppressing IFN-beta synthesis, which it achieves by interfering with the DDX58/IFIH1 (RIG-I/MDA5) pathway. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Protein 2BC]: Affects membrane integrity and causes an increase in membrane permeability. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Protein 2C]: Associates with and induces structural rearrangements of intracellular membranes. Displays RNA-binding activity. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Protein 3ABC]: The precursor 3ABC is targeted to the mitochondrial membrane where protease 3C activity cleaves and inhibits the host antiviral protein MAVS, thereby disrupting activation of IRF3 through the IFIH1/MDA5 pathway. In vivo, the protease activity of 3ABC precursor is more efficient in cleaving the 2BC precursor than that of protein 3C. The 3ABC precursor may therefore play a role in the proteolytic processing of the polyprotein. Possible viroporin. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Protein 3AB]: Interacts with the 3CD precursor and with RNA structures found at both the 5'- and 3'-termini of the viral genome. Since the 3AB precursor contains the hydrophobic domain 3A, it probably anchors the whole viral replicase complex to intracellular membranes on which viral RNA synthesis occurs. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Protein 3A]: May serve as membrane anchor to the 3AB and 3ABC precursors via its hydrophobic domain. May interact with RNA. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Viral protein genome-linked]: Acts as a primer for viral RNA replication and remains covalently bound to viral genomic RNA. VPg is uridylylated prior to priming replication into VPg-pUpU. The VPg-pUpU is then used as primer on the genomic RNA poly(A) by the RNA-dependent RNA polymerase to replicate the viral genome. {ECO:0000250|UniProtKB:P03300, ECO:0000250|UniProtKB:P08617}.; FUNCTION: [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. Cleaves IKBKG/NEMO to impair innate immune signaling. Cleaves host PABPC1 which may participate in the switch of viral translation to RNA synthesis. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: [Protein 3CD]: Interacts with the 3AB precursor and with RNA structures found at both the 5'- and 3'-termini of the viral genome. Disrupts TLR3 signaling by degrading the host adapter protein TICAM1/TRIF. {ECO:0000250|UniProtKB:P08617}.; FUNCTION: RNA-directed RNA polymerase 3D-POL replicates genomic and antigenomic RNA by recognizing replications specific signals. {ECO:0000250|UniProtKB:P08617}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 1230..1237; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00551 |
| Features | Active site (3); Chain (19); Coiled coil (1); Disulfide bond (1); Domain (3); Modified residue (1); Motif (2); Natural variant (43); Nucleotide binding (1); Region (2); Site (11); Transmembrane (2) |
| Keywords | ATP-binding;Capsid protein;Coiled coil;Covalent protein-RNA linkage;Disulfide bond;Helicase;Host cytoplasm;Host cytoplasmic vesicle;Host endosome;Host membrane;Host mitochondrion;Host mitochondrion outer membrane;Host-virus interaction;Hydrolase;Inhibition of host MAVS by virus;Inhibition of host RLR pathway by virus;Inhibition of host innate immune response by virus;Interferon antiviral system evasion;Ion channel;Ion transport;Membrane;Nucleotide-binding;Nucleotidyltransferase;Phosphoprotein;Protease;RNA-binding;RNA-directed RNA polymerase;T=pseudo3 icosahedral capsid protein;Thiol protease;Transferase;Transmembrane;Transmembrane helix;Transport;Viral RNA replication;Viral attachment to host cell;Viral immunoevasion;Viral ion channel;Virion;Virus entry into host cell |
| Interact With | |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: [Capsid protein VP2]: Virion {ECO:0000250|UniProtKB:P08617}. Host endosome, host multivesicular body {ECO:0000250|UniProtKB:P08617}. Note=The egress of newly formed virions occurs through an exosome-like mechanism involving endosomal budding of viral capsids into multivesicular bodies. {ECO:0000250|UniProtKB:P08617}.; SUBCELLULAR LOCATION: [Capsid protein VP3]: Virion {ECO:0000250|UniProtKB:P08617}. Host endosome, host multivesicular body {ECO:0000250|UniProtKB:P08617}. Note=The egress of newly formed virions occurs through an exosome-like mechanism involving endosomal budding of viral capsids into multivesicular bodies. {ECO:0000250|UniProtKB:P08617}.; SUBCELLULAR LOCATION: [Capsid protein VP1]: Virion {ECO:0000250|UniProtKB:P08617}. Host endosome, host multivesicular body {ECO:0000250|UniProtKB:P08617}. Note=The egress of newly formed virions occurs through an exosome-like mechanism involving endosomal budding of viral capsids into multivesicular bodies. {ECO:0000250|UniProtKB:P08617}.; SUBCELLULAR LOCATION: [Capsid protein VP4]: Virion {ECO:0000250|UniProtKB:P08617}. Note=Present in the full mature virion. The egress of newly formed virions occurs through an exosome-like mechanism involving endosomal budding of viral capsids into multivesicular bodies. {ECO:0000250|UniProtKB:P08617}.; SUBCELLULAR LOCATION: [Protein 2B]: Host membrane {ECO:0000250|UniProtKB:P08617}; Peripheral membrane protein {ECO:0000250|UniProtKB:P08617}. Note=Probably localizes to intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. {ECO:0000250|UniProtKB:P08617}.; SUBCELLULAR LOCATION: [Protein 2C]: Host membrane {ECO:0000250|UniProtKB:P08617}; Single-pass membrane protein {ECO:0000250|UniProtKB:P08617}. Note=Probably localizes to intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. May associate with membranes through a N-terminal amphipathic helix. {ECO:0000250|UniProtKB:P08617}.; SUBCELLULAR LOCATION: [Protein 3ABC]: Host membrane {ECO:0000250|UniProtKB:P08617}; Single-pass membrane protein {ECO:0000255}. Host mitochondrion outer membrane {ECO:0000250|UniProtKB:P08617}; Single-pass membrane protein {ECO:0000250|UniProtKB:P08617}. Note=Probably localizes to intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. {ECO:0000250|UniProtKB:P08617}.; SUBCELLULAR LOCATION: [Protein 3AB]: Host membrane {ECO:0000250|UniProtKB:P08617}; Single-pass membrane protein {ECO:0000255}. Note=Probably localizes to intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. {ECO:0000250|UniProtKB:P08617}.; SUBCELLULAR LOCATION: [Protein 3A]: Host membrane {ECO:0000250|UniProtKB:P08617}; Single-pass membrane protein {ECO:0000255}. Note=Probably localizes to intracellular membrane vesicles that are induced after virus infection as the site for viral RNA replication. {ECO:0000250|UniProtKB:P08617}.; SUBCELLULAR LOCATION: [Viral protein genome-linked]: Virion {ECO:0000250|UniProtKB:P08617}.; SUBCELLULAR LOCATION: [Protease 3C]: Host cytoplasm {ECO:0000250|UniProtKB:P08617}.; SUBCELLULAR LOCATION: [RNA-directed RNA polymerase 3D-POL]: Host cytoplasmic vesicle membrane {ECO:0000250|UniProtKB:P08617}; Peripheral membrane protein {ECO:0000250|UniProtKB:P08617}; Cytoplasmic side {ECO:0000250|UniProtKB:P08617}. Note=Interacts with membranes in a complex with viral protein 3AB. 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. {ECO:0000250|UniProtKB:P08617}. |
| Modified Residue | MOD_RES 1499; /note=O-(5'-phospho-RNA)-tyrosine; /evidence=ECO:0000250 |
| Post Translational Modification | PTM: [Genome polyprotein]: Specific enzymatic cleavages by viral protease in vivo yield a variety of precursors and mature proteins. Polyprotein processing intermediates are produced, such as P1-2A which is a functional precursor of the structural proteins, VP0 which is a VP4-VP2 precursor, VP1-2A precursor, 3ABC precursor which is a stable and catalytically active precursor of 3A, 3B and 3C proteins, 3AB and 3CD precursors. The assembly signal 2A is removed from VP1-2A by a host protease, possibly host Cathepsin L. This cleavage occurs over a region of 3 amino-acids probably generating VP1 proteins with heterogeneous C-termini. {ECO:0000250|UniProtKB:P08617}.; PTM: Capsid protein VP0: During virion maturation, immature virions are rendered infectious following cleavage of VP0 into VP4 and VP2. This maturation seems to be an autocatalytic event triggered by the presence of RNA in the capsid and is followed by a conformational change of the particle. {ECO:0000250|UniProtKB:P03303}.; PTM: [Protein VP1-2A]: The assembly signal 2A is removed from VP1-2A by a host protease, possibly host Cathepsin L in nacked virions. This cleavage does not occur in enveloped virions. This cleavage occurs over a region of 3 amino-acids probably generating VP1 proteins with heterogeneous C-termini. {ECO:0000250|UniProtKB:P08617}.; PTM: [Viral protein genome-linked]: VPg is uridylylated prior to priming replication into VPg-pUpU. {ECO:0000250|UniProtKB:P03300}.; PTM: [Capsid protein VP4]: Unlike other picornaviruses, does not seem to be myristoylated. {ECO:0000250|UniProtKB:P08617}. |
| Signal Peptide | |
| Structure 3D | |
| Cross Reference PDB | - |
| Mapped Pubmed ID | - |
| Motif | MOTIF 167..171; /note=(L)YPX(n)L motif; /evidence=ECO:0000250|UniProtKB:P08617; MOTIF 200..205; /note=(L)YPX(n)L motif; /evidence=ECO:0000250|UniProtKB:P08617 |
| Gene Encoded By | |
| Mass | 251,399 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:21248; RHEA:23680 |
| Cross Reference Brenda |