| IED ID | IndEnz0002013669 |
| Enzyme Type ID | protease013669 |
| Protein Name |
Serine/threonine-protein kinase TBK1 EC 2.7.11.1 NF-kappa-B-activating kinase T2K TANK-binding kinase 1 |
| Gene Name | TBK1 NAK |
| 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 | MQSTSNHLWLLSDILGQGATANVFRGRHKKTGDLFAIKVFNNISFLRPVDVQMREFEVLKKLNHKNIVKLFAIEEETTTRHKVLIMEFCPCGSLYTVLEEPSNAYGLPESEFLIVLRDVVGGMNHLRENGIVHRDIKPGNIMRVIGEDGQSVYKLTDFGAARELEDDEQFVSLYGTEEYLHPDMYERAVLRKDHQKKYGATVDLWSIGVTFYHAATGSLPFRPFEGPRRNKEVMYKIITGKPSGAISGVQKAENGPIDWSGDMPVSCSLSRGLQVLLTPVLANILEADQEKCWGFDQFFAETSDILHRMVIHVFSLQQMTAHKIYIHSYNTATIFHELVYKQTKIISSNQELIYEGRRLVLEPGRLAQHFPKTTEENPIFVVSREPLNTIGLIYEKISLPKVHPRYDLDGDASMAKAITGVVCYACRIASTLLLYQELMRKGIRWLIELIKDDYNETVHKKTEVVITLDFCIRNIEKTVKVYEKLMKINLEAAELGEISDIHTKLLRLSSSQGTIETSLQDIDSRLSPGGSLADAWAHQEGTHPKDRNVEKLQVLLNCMTEIYYQFKKDKAERRLAYNEEQIHKFDKQKLYYHATKAMTHFTDECVKKYEAFLNKSEEWIRKMLHLRKQLLSLTNQCFDIEEEVSKYQEYTNELQETLPQKMFTASSGIKHTMTPIYPSSNTLVEMTLGMKKLKEEMEGVVKELAENNHILERFGSLTMDGGLRNVDCL |
| Enzyme Length | 729 |
| Uniprot Accession Number | Q9UHD2 |
| Absorption | |
| Active Site | ACT_SITE 135; /note="Proton acceptor"; /evidence="ECO:0000305|PubMed:23453971, ECO:0000305|PubMed:23453972, ECO:0000305|PubMed:30842653" |
| Activity Regulation | |
| Binding Site | BINDING 38; /note=ATP; /evidence=ECO:0000305 |
| Calcium Binding | |
| catalytic Activity | CATALYTIC ACTIVITY: Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-[protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616, ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:14703513, ECO:0000269|PubMed:15367631, ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21270402, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:21617041, ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:31709703}; CATALYTIC ACTIVITY: Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060, Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013, ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216; EC=2.7.11.1; Evidence={ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:14703513, ECO:0000269|PubMed:15367631, ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21270402, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:21617041, ECO:0000269|PubMed:25636800}; |
| DNA Binding | |
| EC Number | 2.7.11.1 |
| Enzyme Function | FUNCTION: Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents (PubMed:12692549, PubMed:14703513, PubMed:18583960, PubMed:12702806, PubMed:15367631, PubMed:10581243, PubMed:11839743, PubMed:15485837, PubMed:21138416, PubMed:25636800, PubMed:23453971, PubMed:23453972, PubMed:23746807, PubMed:26611359, PubMed:32404352). Following activation of toll-like receptors by viral or bacterial components, associates with TRAF3 and TANK and phosphorylates interferon regulatory factors (IRFs) IRF3 and IRF7 as well as DDX3X (PubMed:12692549, PubMed:14703513, PubMed:18583960, PubMed:12702806, PubMed:15367631, PubMed:25636800). This activity allows subsequent homodimerization and nuclear translocation of the IRFs leading to transcriptional activation of pro-inflammatory and antiviral genes including IFNA and IFNB (PubMed:12702806, PubMed:15367631, PubMed:25636800, PubMed:32972995). In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli (PubMed:23453971, PubMed:23453972, PubMed:23746807). Plays a key role in IRF3 activation: acts by first phosphorylating innate adapter proteins MAVS, STING1 and TICAM1 on their pLxIS motif, leading to recruitment of IRF3, thereby licensing IRF3 for phosphorylation by TBK1 (PubMed:25636800, PubMed:30842653). Phosphorylated IRF3 dissociates from the adapter proteins, dimerizes, and then enters the nucleus to induce expression of interferons (PubMed:25636800). Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes (PubMed:21931631). Under particular conditions, functions as a NF-kappa-B effector by phosphorylating NF-kappa-B inhibitor alpha/NFKBIA, IKBKB or RELA to translocate NF-Kappa-B to the nucleus (PubMed:10783893, PubMed:15489227). Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy (PubMed:21617041). Phosphorylates SMCR8 component of the C9orf72-SMCR8 complex, promoting autophagosome maturation (PubMed:27103069). Phosphorylates ATG8 proteins MAP1LC3C and GABARAPL2, thereby preventing their delipidation and premature removal from nascent autophagosomes (PubMed:31709703). Phosphorylates and activates AKT1 (PubMed:21464307). Seems to play a role in energy balance regulation by sustaining a state of chronic, low-grade inflammation in obesity, wich leads to a negative impact on insulin sensitivity (By similarity). Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C (PubMed:21270402). Phosphorylates Borna disease virus (BDV) P protein (PubMed:16155125). Plays an essential role in the TLR3- and IFN-dependent control of herpes virus HSV-1 and HSV-2 infections in the central nervous system (PubMed:22851595). {ECO:0000250|UniProtKB:Q9WUN2, ECO:0000269|PubMed:10581243, ECO:0000269|PubMed:10783893, ECO:0000269|PubMed:11839743, ECO:0000269|PubMed:12692549, ECO:0000269|PubMed:12702806, ECO:0000269|PubMed:14703513, ECO:0000269|PubMed:15367631, ECO:0000269|PubMed:15485837, ECO:0000269|PubMed:15489227, ECO:0000269|PubMed:16155125, ECO:0000269|PubMed:18583960, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:21270402, ECO:0000269|PubMed:21464307, ECO:0000269|PubMed:21617041, ECO:0000269|PubMed:21931631, ECO:0000269|PubMed:22851595, ECO:0000269|PubMed:23453971, ECO:0000269|PubMed:23453972, ECO:0000269|PubMed:23746807, ECO:0000269|PubMed:25636800, ECO:0000269|PubMed:26611359, ECO:0000269|PubMed:27103069, ECO:0000269|PubMed:30842653, ECO:0000269|PubMed:31709703, ECO:0000269|PubMed:32972995}. |
| Temperature Dependency | |
| PH Dependency | |
| Pathway | |
| nucleotide Binding | NP_BIND 15..23; /note=ATP; /evidence=ECO:0000255|PROSITE-ProRule:PRU00159 |
| Features | Active site (1); Beta strand (24); Binding site (1); Chain (1); Coiled coil (2); Cross-link (3); Domain (2); Erroneous initiation (1); Helix (25); Modified residue (2); Mutagenesis (28); Natural variant (34); Nucleotide binding (1); Region (1); Turn (7) |
| Keywords | 3D-structure;ATP-binding;Amyotrophic lateral sclerosis;Antiviral defense;Coiled coil;Cytoplasm;Disease variant;Glaucoma;Host-virus interaction;Immunity;Innate immunity;Isopeptide bond;Kinase;Neurodegeneration;Nucleotide-binding;Phosphoprotein;Reference proteome;Serine/threonine-protein kinase;Transferase;Ubl conjugation |
| Interact With | Q9UKV8; Q7Z3C6; Q9H6S1; Q13137; Q6DT37; P08238; Q9Y6W8; Q14164; Q9Y6K9; Q14653; Q92985; Q7Z434; Q86YT6; Q96AX9; Q9NVV4; Q96CV9; O14730; P42226; Q86WV6; Q92844; A7MCY6; Q8IUC6; Q12933; Q13114; O95801; P40222; Q62167; O41932; P0DTC5; P59596; P0DTD1; Q60803; Q8BHN1; Q05127; I0DF37; I6W9F2; K7Y1A2; P27958; P27958 |
| Induction | |
| Subcellular Location | SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15485837, ECO:0000269|PubMed:21813773, ECO:0000269|PubMed:29251827}. Note=Upon mitogen stimulation or triggering of the immune system, TBK1 is recruited to the exocyst by EXOC2. {ECO:0000269|PubMed:17018283}. |
| Modified Residue | MOD_RES 172; /note="Phosphoserine; by autocatalysis and IKKB"; /evidence="ECO:0000269|PubMed:11839743, ECO:0000269|PubMed:22851595, ECO:0000269|PubMed:23746807"; MOD_RES 716; /note="Phosphoserine"; /evidence="ECO:0007744|PubMed:23186163" |
| Post Translational Modification | PTM: Autophosphorylation at Ser-172 activates the kinase, and is an essential step for virus-triggered signaling. Phosphorylated by IKBKB/IKKB at Ser-172. Phosphorylation requires homodimerization and ubiquitination at Lys-30 and Lys-401. Dephosphorylated at Ser-172 by PPM1B and this negatively regulates its role in mediating antiviral response. {ECO:0000269|PubMed:11839743, ECO:0000269|PubMed:21138416, ECO:0000269|PubMed:23453971, ECO:0000269|PubMed:23746807}.; PTM: 'Lys-63'-linked polyubiquitination by MIB1 after RNA virus infection, or by NRDP1 after LPS stimulation at Lys-30 and Lys-401, participates in kinase activation. 'Lys-48'-linked polyubiquitination at Lys-670 by DTX4 leads to proteasomal degradation. 'Lys-48'-linked polyubiquitination by TRAIP also leads to proteasomal degradation. 'Lys-63'-linked polyubiquitination by RNF128 at Lys-30 and Lys-401 leads to the activation of antiviral responses. {ECO:0000269|PubMed:22388039, ECO:0000269|PubMed:23453971, ECO:0000269|PubMed:27776110, ECO:0000269|PubMed:32366851}.; PTM: (Microbial infection) Interaction with SARS-CoV-2 M protein induces 'Lys-48'-linked ubiquitination which leads to proteasomal degradation. {ECO:0000269|PubMed:34084167}. |
| Signal Peptide | |
| Structure 3D | Electron microscopy (1); X-ray crystallography (24) |
| Cross Reference PDB | 4EFO; 4EUT; 4EUU; 4IM0; 4IM2; 4IM3; 4IW0; 4IWO; 4IWP; 4IWQ; 5EOA; 5EOF; 5EP6; 5W5V; 6BNY; 6BOD; 6BOE; 6CQ0; 6CQ4; 6CQ5; 6NT9; 6O8B; 6RSR; 6RST; 6RSU; |
| Mapped Pubmed ID | 10421793; 12133833; 14517278; 14743216; 15210742; 15361868; 15619605; 16153868; 16223731; 16306936; 16380379; 16394098; 16537515; 16846591; 16887178; 16888014; 16914100; 16973572; 17047224; 17157040; 17327220; 17526488; 17568778; 17618271; 17721511; 17823124; 18307994; 18353649; 18356163; 18508731; 18818105; 18977754; 19017982; 19307177; 19380831; 19433799; 19479062; 19615732; 19776740; 19847166; 19926846; 19955181; 19958770; 20098747; 20304918; 20331378; 20562859; 20588308; 20711500; 21048031; 21212807; 21332394; 21364999; 21492457; 21782231; 21868362; 21931555; 21939555; 21988832; 22000020; 22127978; 22171259; 22394562; 22579474; 22610919; 22619329; 22787218; 22939624; 23023393; 23096996; 23157677; 23209807; 23286385; 23395611; 23395801; 23396211; 23414517; 23421332; 23542348; 23649622; 23675467; 23836654; 24027431; 24062311; 24189400; 24255178; 24335286; 24349538; 24449872; 24468793; 24478431; 24549848; 24560620; 24606918; 24643253; 24695225; 24696485; 24699864; 24706939; 24722368; 24752990; 24807708; 24872591; 24962318; 25070846; 25142606; 25284765; 25297994; 25303530; 25503978; 25531185; 25606824; 25700176; 25780039; 25815785; 25855743; 25891802; 25923723; 25939384; 25972374; 26350399; 26376340; 26407194; 26476236; 26581300; 26638075; 26656453; 26674655; 26915459; 26976762; 27035970; 27086836; 27123832; 27135603; 27145266; 27156075; 27211305; 27234299; 27247382; 27260353; 27350692; 27355837; 27370208; 27538435; 27568284; 27570907; 27620379; 27881886; 27892983; 27935834; 27939697; 28008748; 28025332; 28049762; 28119118; 28159912; 28188292; 28282485; 28346439; 28365590; 28487378; 28676338; 28716898; 28822984; 28848048; 28954889; 28984711; 29103041; 29125880; 29137817; 29138248; 29349657; 29379028; 29394115; 29398122; 29559975; 29653159; 29673738; 29743353; 29743370; 29755980; 29797567; 29886477; 30021902; 30033073; 30082428; 30183071; 30196251; 30270002; 30296527; 30349097; 30404831; 30420664; 30504235; 30530224; 30627666; 30672142; 30769920; 30827897; 30853401; 30867315; 30912981; 30995277; 31113902; 31114588; 31118511; 31189704; 31235549; 31256920; 31379806; 31442668; 31451663; 31498468; 31509299; 31577952; 31662325; 31748271; 31810986; 31818880; 31859507; 31987900; 32034138; 32079994; 32159970; 32238587; 32268090; 32284536; 32298923; 32413959; 32514015; 32581130; 32696476; 32757223; 32772249; 32814047; 32835772; 32858764; 32893041; 32980182; 33078349; 33168920; 33171123; 33310066; 33397830; 33411856; 33548116; 33679751; 33767151; 33858962; 33965374; 34081168; 34099552; 34226595; 34248923; 34260286; 34363755; 34518217; 34759016; 34903664; 9463386; 9566918; |
| Motif | |
| Gene Encoded By | |
| Mass | 83,642 |
| Kinetics | |
| Metal Binding | |
| Rhea ID | RHEA:17989; RHEA:46608 |
| Cross Reference Brenda |