| IED ID | IndEnz0002004645 |
| Enzyme Type ID | protease004645 |
| Protein Name |
Interferon-induced helicase C domain-containing protein 1 EC 3.6.4.13 Clinically amyopathic dermatomyositis autoantigen 140 kDa CADM-140 autoantigen Helicase with 2 CARD domains Helicard Interferon-induced with helicase C domain protein 1 Melanoma differentiation-associated protein 5 MDA-5 Murabutide down-regulated protein RIG-I-like receptor 2 RLR-2 RNA helicase-DEAD box protein 116 |
| Gene Name | IFIH1 MDA5 RH116 |
| Organism | Homo sapiens (Human) |
| Taxonomic Lineage | cellular organisms Eukaryota Opisthokonta Metazoa Eumetazoa Bilateria Deuterostomia Chordata Craniata Vertebrata Gnathostomata (jawed vertebrates) Teleostomi Euteleostomi Sarcopterygii Dipnotetrapodomorpha Tetrapoda Amniota Mammalia Theria Eutheria Boreoeutheria Euarchontoglires Primates Haplorrhini Simiiformes Catarrhini Hominoidea (apes) Hominidae (great apes) Homininae Homo Homo sapiens (Human) |
| Enzyme Sequence | MSNGYSTDENFRYLISCFRARVKMYIQVEPVLDYLTFLPAEVKEQIQRTVATSGNMQAVELLLSTLEKGVWHLGWTREFVEALRRTGSPLAARYMNPELTDLPSPSFENAHDEYLQLLNLLQPTLVDKLLVRDVLDKCMEEELLTIEDRNRIAAAENNGNESGVRELLKRIVQKENWFSAFLNVLRQTGNNELVQELTGSDCSESNAEIENLSQVDGPQVEEQLLSTTVQPNLEKEVWGMENNSSESSFADSSVVSESDTSLAEGSVSCLDESLGHNSNMGSDSGTMGSDSDEENVAARASPEPELQLRPYQMEVAQPALEGKNIIICLPTGSGKTRVAVYIAKDHLDKKKKASEPGKVIVLVNKVLLVEQLFRKEFQPFLKKWYRVIGLSGDTQLKISFPEVVKSCDIIISTAQILENSLLNLENGEDAGVQLSDFSLIIIDECHHTNKEAVYNNIMRHYLMQKLKNNRLKKENKPVIPLPQILGLTASPGVGGATKQAKAEEHILKLCANLDAFTIKTVKENLDQLKNQIQEPCKKFAIADATREDPFKEKLLEIMTRIQTYCQMSPMSDFGTQPYEQWAIQMEKKAAKEGNRKERVCAEHLRKYNEALQINDTIRMIDAYTHLETFYNEEKDKKFAVIEDDSDEGGDDEYCDGDEDEDDLKKPLKLDETDRFLMTLFFENNKMLKRLAENPEYENEKLTKLRNTIMEQYTRTEESARGIIFTKTRQSAYALSQWITENEKFAEVGVKAHHLIGAGHSSEFKPMTQNEQKEVISKFRTGKINLLIATTVAEEGLDIKECNIVIRYGLVTNEIAMVQARGRARADESTYVLVAHSGSGVIEHETVNDFREKMMYKAIHCVQNMKPEEYAHKILELQMQSIMEKKMKTKRNIAKHYKNNPSLITFLCKNCSVLACSGEDIHVIEKMHHVNMTPEFKELYIVRENKALQKKCADYQINGEIICKCGQAWGTMMVHKGLDLPCLKIRNFVVVFKNNSTKKQYKKWVELPITFPNLDYSECCLFSDED |
| Enzyme Length | 1025 |
| Uniprot Accession Number | Q9BYX4 |
| Absorption | |
| Active Site | |
| Activity Regulation | |
| Binding Site | |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + H2O = ADP + H(+) + phosphate; Xref=Rhea:RHEA:13065, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:43474, ChEBI:CHEBI:456216; EC=3.6.4.13; |
| DNA Binding | |
| EC Number | 3.6.4.13 |
| Enzyme Function | FUNCTION: Innate immune receptor which acts as a cytoplasmic sensor of viral nucleic acids and plays a major role in sensing viral infection and in the activation of a cascade of antiviral responses including the induction of type I interferons and proinflammatory cytokines (PubMed:33727702). Its ligands include mRNA lacking 2'-O-methylation at their 5' cap and long-dsRNA (>1 kb in length). Upon ligand binding it associates with mitochondria antiviral signaling protein (MAVS/IPS1) which activates the IKK-related kinases: TBK1 and IKBKE which phosphorylate interferon regulatory factors: IRF3 and IRF7 which in turn activate transcription of antiviral immunological genes, including interferons (IFNs); IFN-alpha and IFN-beta. Responsible for detecting the Picornaviridae family members such as encephalomyocarditis virus (EMCV) and mengo encephalomyocarditis virus (ENMG). Detects coronavirus SARS-CoV-2 (PubMed:33440148, PubMed:33514628). Can also detect other viruses such as dengue virus (DENV), west Nile virus (WNV), and reovirus. Also involved in antiviral signaling in response to viruses containing a dsDNA genome, such as vaccinia virus. Plays an important role in amplifying innate immune signaling through recognition of RNA metabolites that are produced during virus infection by ribonuclease L (RNase L). May play an important role in enhancing natural killer cell function and may be involved in growth inhibition and apoptosis in several tumor cell lines. {ECO:0000269|PubMed:14645903, ECO:0000269|PubMed:19211564, ECO:0000269|PubMed:19656871, ECO:0000269|PubMed:21217758, ECO:0000269|PubMed:21742966, ECO:0000269|PubMed:29117565, ECO:0000269|PubMed:33440148, ECO:0000269|PubMed:33514628, ECO:0000269|PubMed:33727702}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | |
| Features | Alternative sequence (2); Beta strand (16); Chain (1); Compositional bias (2); Cross-link (2); Domain (5); Erroneous initiation (1); Helix (15); Metal binding (4); Modified residue (6); Mutagenesis (13); Natural variant (12); Region (2); Sequence caution (1); Sequence conflict (6); Site (3); Turn (5) |
| Keywords | 3D-structure;ATP-binding;Aicardi-Goutieres syndrome;Alternative splicing;Antiviral defense;Cytoplasm;Diabetes mellitus;Disease variant;Helicase;Host-virus interaction;Hydrolase;Immunity;Innate immunity;Isopeptide bond;Metal-binding;Mitochondrion;Nucleotide-binding;Nucleus;Phosphoprotein;RNA-binding;Reference proteome;Repeat;Ubl conjugation;Zinc |
| Interact With | Itself; Q14164; P05161; Q14145; Q7Z434; Q7Z434-1; O75569; O14730; Q96EQ8; Q3LXA3; P0DTC5; P0C774; P11207; P30927; Q9EMA9; P0DTD1; P04487 |
| Induction | INDUCTION: By interferon (IFN) and TNF. {ECO:0000269|PubMed:11805321}. |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11805321, ECO:0000269|PubMed:14645903, ECO:0000269|PubMed:33727702}. Nucleus {ECO:0000305}. Mitochondrion {ECO:0000269|PubMed:33727702}. Note=Upon viral RNA stimulation and ISGylation, translocates from cytosol to mitochondrion. May be found in the nucleus, during apoptosis. |
| Modified Residue | MOD_RES 88; /note=Phosphoserine; /evidence=ECO:0000269|PubMed:33727702; MOD_RES 289; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q8R5F7; MOD_RES 291; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q8R5F7; MOD_RES 301; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q8R5F7; MOD_RES 645; /note=Phosphoserine; /evidence=ECO:0000250|UniProtKB:Q8R5F7; MOD_RES 828; /note=Phosphoserine; by RIOK3; /evidence=ECO:0000269|PubMed:25865883 |
| Post Translational Modification | PTM: Sumoylated. Sumoylation positively regulates its role in type I interferon induction and is enhanced by PIAS2-beta. {ECO:0000269|PubMed:21156324}.; PTM: Ubiquitinated by RNF125, leading to its degradation by the proteasome (PubMed:17460044). USP17/UPS17L2-dependent deubiquitination positively regulates the receptor (PubMed:20368735). Ubiquitinated by TRIM25 via 'Lys-63'-linked ubiquitination, promoting activation of IFIH1/MDA5 (PubMed:30193849). Ubiquitinated by TRIM40 via 'Lys-48'-linked ubiquitination; leading to proteasomal degradation (PubMed:29117565). {ECO:0000269|PubMed:17460044, ECO:0000269|PubMed:20368735, ECO:0000269|PubMed:29117565, ECO:0000269|PubMed:30193849}.; PTM: ISGylated by ISG15. ISGylation increases upon infection with dengue (DENV) or Zika (ZIKV) viruses. ISGylation at Lys-23 and Lys-43 is dependent of dephosphorylation at Ser-88, regulates mitochondrial translocation and oligomerization. Essential for IFIH1/MDA5-mediated cytokine responses and restriction of virus replication. {ECO:0000269|PubMed:33727702}.; PTM: Phosphorylated at Ser-88. Dephosphorylated by phsophatases PP1; dephosphorylation precedes and is required for ISGylation. {ECO:0000269|PubMed:33727702}.; PTM: During apoptosis, processed into 3 cleavage products. The helicase-containing fragment, once liberated from the CARD domains, translocate from the cytoplasm to the nucleus. The processed protein significantly sensitizes cells to DNA degradation. {ECO:0000250|UniProtKB:Q8R5F7}.; PTM: (Microbial infection) Cleaved and inactivated by the protease 2A of coxsackievirus B3, poliovirus and enterovirus 71 allowing the virus to disrupt the host type I interferon production. {ECO:0000269|PubMed:24390337}. |
| Signal Peptide | |
| Structure 3D | NMR spectroscopy (1); Electron microscopy (4); X-ray crystallography (3) |
| Cross Reference PDB | 2RQB; 3B6E; 3GA3; 4GL2; 7DNI; 7DNJ; 7JL0; 7JL2; |
| Mapped Pubmed ID | 10421793; 10581243; 11002417; 11717445; 12107169; 12133833; 12221085; 12692549; 12884866; 14676839; 14703513; 15361868; 16116171; 16125763; 16153868; 16281057; 16306936; 16575407; 16585540; 16618810; 16782388; 16797201; 16846591; 16858409; 16914100; 16963558; 17190786; 17267501; 17327220; 17442111; 17526488; 17535987; 17541283; 17554260; 17991829; 18026693; 18071670; 18285833; 18307765; 18591409; 18684960; 18761323; 18927125; 18984593; 19016379; 19073967; 19154402; 19156166; 19164550; 19188362; 19264985; 19324880; 19403670; 19430480; 19450885; 19479062; 19539001; 19615405; 19620789; 19666475; 19668221; 19742420; 19797678; 19838195; 19841890; 19846522; 19890046; 19893624; 19913121; 19951419; 19961590; 20033399; 20116863; 20228808; 20467774; 20538742; 20595247; 20628086; 20644636; 20647273; 20668468; 20694011; 20719949; 20736039; 20739519; 20844740; 20953190; 21052763; 21071089; 21113677; 21123378; 21187438; 21224721; 21245912; 21270278; 21289206; 21342182; 21496705; 21705624; 21844166; 21903422; 21911578; 22046141; 22053898; 22110759; 22152027; 22185736; 22192091; 22461656; 22590509; 22619329; 22623778; 22705106; 22732950; 22789000; 22797917; 22810585; 22864531; 22886382; 22892369; 22915805; 23090998; 23108955; 23144876; 23152520; 23246693; 23273991; 23390110; 23390309; 23436757; 23441136; 23453971; 23499489; 23535865; 23650567; 23671710; 23684765; 23734776; 23926323; 24039580; 24117221; 24386202; 24402011; 24522921; 24550253; 24621100; 24701034; 24719229; 24722368; 24741583; 24800889; 24829334; 24886842; 24960033; 25042601; 25127512; 25130193; 25151986; 25288302; 25331610; 25463548; 25515714; 25579795; 25794939; 25850761; 25878102; 25891073; 25903820; 26208481; 26215161; 26284909; 26351918; 26385483; 26485346; 26496610; 26564103; 26646717; 26782418; 26833990; 26893477; 27130701; 27643693; 27655134; 27813554; 28000722; 28090671; 28234905; 28250012; 28319323; 28414768; 28475458; 28483922; 28501801; 28553952; 28560754; 28594402; 28606988; 28659477; 28716935; 28760879; 28768856; 28929635; 28940253; 28974542; 28983955; 29186193; 29229575; 29380533; 29395326; 29429386; 29462185; 29698627; 29753657; 29899107; 29930297; 29997212; 30130154; 30177393; 30219631; 30286211; 30304915; 30449722; 30449789; 30451863; 30633820; 30742689; 30761886; 31427910; 31440940; 31539314; 31733941; 31772029; 31866997; 31898846; 32057771; 32202700; 32311159; 32360518; 32471869; 32571931; 32603639; 32737579; 32829203; 33140045; 33299896; 33323678; 33372174; 33373584; 33387195; 33519803; 33740622; 33983939; 34101213; 34185153; 34189822; 34211037; 34249006; 34726731; 34772806; 34795277; 34882124; 9008162; 9463386; 9689078; |
| Motif | |
| Gene Encoded By | |
| Mass | 116,689 |
| Kinetics | |
| Metal Binding | METAL 907; /note=Zinc; /evidence=ECO:0000255|PROSITE-ProRule:PRU01125; METAL 910; /note=Zinc; /evidence=ECO:0000255|PROSITE-ProRule:PRU01125; METAL 962; /note=Zinc; /evidence=ECO:0000255|PROSITE-ProRule:PRU01125; METAL 964; /note=Zinc; /evidence=ECO:0000255|PROSITE-ProRule:PRU01125 |
| Rhea ID | RHEA:13065 |
| Cross Reference Brenda |