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Protein

Serine/threonine-protein kinase TBK1

Gene

Tbk1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents. 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. 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. In order to establish such an antiviral state, TBK1 form several different complexes whose composition depends on the type of cell and cellular stimuli. Thus, several scaffolding molecules including FADD, TRADD, MAVS, AZI2, TANK or TBKBP1/SINTBAD can be recruited to the TBK1-containing-complexes. 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. Restricts bacterial proliferation by phosphorylating the autophagy receptor OPTN/Optineurin on 'Ser-177', thus enhancing LC3 binding affinity and antibacterial autophagy. Phosphorylates and activates AKT1. 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.4 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Enzyme regulationi

Kinase activity is inhibited competitively by amlexanox.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei38ATPPROSITE-ProRule annotation1
Active sitei135Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi15 – 23ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • nucleic acid binding Source: MGI
  • phosphoprotein binding Source: MGI
  • protein serine/threonine kinase activity Source: ParkinsonsUK-UCL

GO - Biological processi

  • activation of innate immune response Source: MGI
  • defense response to Gram-positive bacterium Source: MGI
  • defense response to virus Source: UniProtKB-KW
  • dendritic cell proliferation Source: MGI
  • innate immune response Source: UniProtKB-KW
  • negative regulation of gene expression Source: UniProtKB
  • peptidyl-serine phosphorylation Source: ParkinsonsUK-UCL
  • positive regulation of I-kappaB kinase/NF-kappaB signaling Source: Ensembl
  • positive regulation of interferon-alpha production Source: MGI
  • positive regulation of interferon-beta biosynthetic process Source: MGI
  • positive regulation of interferon-beta production Source: MGI
  • positive regulation of transcription from RNA polymerase II promoter Source: MGI
  • positive regulation of xenophagy Source: ParkinsonsUK-UCL
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Biological processi

Antiviral defense, Immunity, Innate immunity

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

ReactomeiR-MMU-1606341. IRF3 mediated activation of type 1 IFN.
R-MMU-3134975. Regulation of innate immune responses to cytosolic DNA.
R-MMU-3249367. STAT6-mediated induction of chemokines.
R-MMU-3270619. IRF3-mediated induction of type I IFN.
R-MMU-936440. Negative regulators of RIG-I/MDA5 signaling.

Names & Taxonomyi

Protein namesi
Recommended name:
Serine/threonine-protein kinase TBK1 (EC:2.7.11.1)
Alternative name(s):
T2K
TANK-binding kinase 1
Gene namesi
Name:Tbk1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 10

Organism-specific databases

MGIiMGI:1929658. Tbk1.

Subcellular locationi

  • Cytoplasm

  • Note: Upon mitogen stimulation or triggering of the immune system, TBK1 is recruited to the exocyst by EXOC2.By similarity

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Disruption phenotypei

Mice display embryonic lethality at E14.5 due to massive liver degeneration and apoptosis. Embryonic fibroblasts from mice lacking Tbk1 exhibit dramatically reduced transcription of NF-kappa-B, as well as marked defects in interferon alpha and beta, and RANTES gene expression after infection with Sendai or Newcastle disease virus.3 Publications

Chemistry databases

ChEMBLiCHEMBL2189160.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000867441 – 729Serine/threonine-protein kinase TBK1Add BLAST729

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Cross-linki30Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei172Phosphoserine; by autocatalysis and IKKB1 Publication1
Cross-linki401Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Cross-linki670Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin)By similarity
Modified residuei716PhosphoserineBy similarity1

Post-translational modificationi

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.1 Publication
'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 (By similarity).By similarity

Keywords - PTMi

Isopeptide bond, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ9WUN2.
MaxQBiQ9WUN2.
PaxDbiQ9WUN2.
PRIDEiQ9WUN2.

PTM databases

iPTMnetiQ9WUN2.
PhosphoSitePlusiQ9WUN2.

Expressioni

Gene expression databases

BgeeiENSMUSG00000020115.
CleanExiMM_TBK1.
ExpressionAtlasiQ9WUN2. baseline and differential.
GenevisibleiQ9WUN2. MM.

Interactioni

Subunit structurei

Homodimer. Interacts with DDX3X, TIRAP and TRAF2. Part of a ternary complex consisting of TANK, TRAF2 and TBK1. Interacts with AZI2, TANK and TBKBP1; these interactions are mutually exclusive and mediate TBK1 activation. Interacts with GSK3B; this interaction promotes TBK1 self-association and autophosphorylation. Interacts with SIKE1; SIKE1 is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection or TLR3 stimulation. Interacts with IRF3 and DDX58/RIG-I. Interacts with CYLD. Interacts with OPTN and TRAF3. Interacts with SRC. Interacts with the exocyst complex subunit SEC5/EXOC2; this interaction is sufficient to trigger TBK1 activity. Interacts with TMEM173/MITA. Interacts with IFIT3 (via N-terminus). Interacts with MAVS only in the presence of IFIT3. Interacts with TICAM1 and this interaction is enhanced in the presence of WDFY1 (By similarity).By similarity1 Publication

Binary interactionsi

WithEntry#Exp.IntActNotes
GAMMAHV.ORF11O419323EBI-764193,EBI-9544132From a different organism.
TankP703476EBI-764193,EBI-646116
Tbkbp1A2A9T02EBI-764193,EBI-7987134
Tmem173Q3TBT33EBI-764193,EBI-3862093

GO - Molecular functioni

Protein-protein interaction databases

BioGridi208009. 17 interactors.
DIPiDIP-29880N.
IntActiQ9WUN2. 12 interactors.
MINTiMINT-111979.
STRINGi10090.ENSMUSP00000020316.

Chemistry databases

BindingDBiQ9WUN2.

Structurei

Secondary structure

1729
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi5 – 14Combined sources10
Beta strandi22 – 28Combined sources7
Turni29 – 31Combined sources3
Beta strandi34 – 39Combined sources6
Helixi49 – 60Combined sources12
Beta strandi70 – 75Combined sources6
Turni77 – 79Combined sources3
Beta strandi82 – 87Combined sources6
Helixi94 – 98Combined sources5
Helixi101 – 103Combined sources3
Helixi109 – 127Combined sources19
Beta strandi128 – 130Combined sources3
Helixi138 – 140Combined sources3
Beta strandi141 – 145Combined sources5
Beta strandi149 – 155Combined sources7
Helixi176 – 179Combined sources4
Helixi182 – 192Combined sources11
Beta strandi194 – 197Combined sources4
Beta strandi200 – 202Combined sources3
Helixi203 – 216Combined sources14
Beta strandi220 – 222Combined sources3
Helixi231 – 239Combined sources9
Beta strandi247 – 249Combined sources3
Beta strandi252 – 254Combined sources3
Beta strandi258 – 262Combined sources5
Helixi271 – 284Combined sources14
Helixi289 – 292Combined sources4
Helixi295 – 307Combined sources13
Beta strandi309 – 315Combined sources7
Turni316 – 319Combined sources4
Beta strandi320 – 326Combined sources7
Beta strandi328 – 330Combined sources3
Helixi332 – 343Combined sources12
Helixi347 – 349Combined sources3
Beta strandi351 – 354Combined sources4
Beta strandi357 – 359Combined sources3
Helixi367 – 369Combined sources3
Beta strandi375 – 377Combined sources3
Beta strandi379 – 382Combined sources4
Helixi408 – 483Combined sources76
Beta strandi484 – 486Combined sources3
Helixi495 – 524Combined sources30
Beta strandi530 – 532Combined sources3
Helixi536 – 539Combined sources4
Helixi544 – 546Combined sources3
Helixi548 – 571Combined sources24
Helixi577 – 644Combined sources68
Helixi645 – 647Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4JL9X-ray3.10A2-656[»]
4JLCX-ray3.00A2-656[»]
ProteinModelPortaliQ9WUN2.
SMRiQ9WUN2.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini9 – 310Protein kinasePROSITE-ProRule annotationAdd BLAST302
Domaini309 – 385Ubiquitin-likeAdd BLAST77

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni621 – 629Interaction with AZI2, TANK and TBKBP1By similarity9

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili407 – 6571 PublicationAdd BLAST251
Coiled coili658 – 713Sequence analysisAdd BLAST56

Domaini

Comprises A N-terminal kinase domain, a ubiquitin-like domain and a C-terminal coiled-coil region mediating homodimerization.1 Publication

Sequence similaritiesi

Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation
Contains 1 ubiquitin-like domain.Curated

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiKOG4250. Eukaryota.
ENOG410XRMU. LUCA.
GeneTreeiENSGT00820000127009.
HOGENOMiHOG000220867.
HOVERGENiHBG008494.
InParanoidiQ9WUN2.
KOiK05410.
OMAiFRGRHKK.
OrthoDBiEOG091G0354.
PhylomeDBiQ9WUN2.
TreeFamiTF324269.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q9WUN2-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MQSTSNHLWL LSDILGQGAT ANVFRGRHKK TGDLYAVKVF NNISFLRPVD
60 70 80 90 100
VQMREFEVLK KLNHKNIVKL FAIEEETTTR HKVLIMEFCP CGSLYTVLEE
110 120 130 140 150
PSNAYGLPES EFLIVLRDVV GGMNHLRENG IVHRDIKPGN IMRVIGEDGQ
160 170 180 190 200
SVYKLTDFGA ARELEDDEQF VSLYGTEEYL HPDMYERAVL RKDHQKKYGA
210 220 230 240 250
TVDLWSVGVT FYHAATGSLP FRPFEGPRRN KEVMYKIITG KPSGAISGVQ
260 270 280 290 300
KAENGPIDWS GDMPLSCSLS QGLQALLTPV LANILEADQE KCWGFDQFFA
310 320 330 340 350
ETSDVLHRMV IHVFSLQHMT AHKIYIHSYN TAAVFHELVY KQTKIVSSNQ
360 370 380 390 400
ELIYEGRRLV LELGRLAQHF PKTTEENPIF VTSREQLNTV GLRYEKISLP
410 420 430 440 450
KIHPRYDLDG DASMAKAVTG VVCYACRTAS TLLLYQELMR KGVRWLVELV
460 470 480 490 500
KDDYNETVHK KTEVVITLDF CIRNIEKTVK VYEKLMKVNL EAAELGEISD
510 520 530 540 550
IHTKLLRLSS SQGTIESSLQ DISSRLSPGG LLADTWAHQE GTHPRDRNVE
560 570 580 590 600
KLQVLLNCIT EIYYQFKKDK AERRLAYNEE QIHKFDKQKL YYHATKAMSH
610 620 630 640 650
FSEECVRKYE AFKDKSEEWM RKMLHLRKQL LSLTNQCFDI EEEVSKYQDY
660 670 680 690 700
TNELQETLPQ KMLAASGGVK HAMAPIYPSS NTLVEMTLGM KKLKEEMEGV
710 720
VKELAENNHI LERFGSLTMD GGLRNVDCL
Length:729
Mass (Da):83,425
Last modified:November 1, 1999 - v1
Checksum:i978ADDE3061DACD1
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti468L → V in BAB23440 (PubMed:16141072).Curated1
Sequence conflicti594A → S in BAB23244 (PubMed:16141072).Curated1
Sequence conflicti631L → S in BAB23440 (PubMed:16141072).Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF191839 mRNA. Translation: AAF05990.1.
AF145705 mRNA. Translation: AAD34590.1.
AK004269 mRNA. Translation: BAB23244.1.
AK004649 mRNA. Translation: BAB23440.1.
CCDSiCCDS24212.1.
RefSeqiNP_062760.3. NM_019786.4.
UniGeneiMm.34580.

Genome annotation databases

EnsembliENSMUST00000020316; ENSMUSP00000020316; ENSMUSG00000020115.
GeneIDi56480.
KEGGimmu:56480.
UCSCiuc007hft.3. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF191839 mRNA. Translation: AAF05990.1.
AF145705 mRNA. Translation: AAD34590.1.
AK004269 mRNA. Translation: BAB23244.1.
AK004649 mRNA. Translation: BAB23440.1.
CCDSiCCDS24212.1.
RefSeqiNP_062760.3. NM_019786.4.
UniGeneiMm.34580.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4JL9X-ray3.10A2-656[»]
4JLCX-ray3.00A2-656[»]
ProteinModelPortaliQ9WUN2.
SMRiQ9WUN2.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi208009. 17 interactors.
DIPiDIP-29880N.
IntActiQ9WUN2. 12 interactors.
MINTiMINT-111979.
STRINGi10090.ENSMUSP00000020316.

Chemistry databases

BindingDBiQ9WUN2.
ChEMBLiCHEMBL2189160.

PTM databases

iPTMnetiQ9WUN2.
PhosphoSitePlusiQ9WUN2.

Proteomic databases

EPDiQ9WUN2.
MaxQBiQ9WUN2.
PaxDbiQ9WUN2.
PRIDEiQ9WUN2.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000020316; ENSMUSP00000020316; ENSMUSG00000020115.
GeneIDi56480.
KEGGimmu:56480.
UCSCiuc007hft.3. mouse.

Organism-specific databases

CTDi29110.
MGIiMGI:1929658. Tbk1.

Phylogenomic databases

eggNOGiKOG4250. Eukaryota.
ENOG410XRMU. LUCA.
GeneTreeiENSGT00820000127009.
HOGENOMiHOG000220867.
HOVERGENiHBG008494.
InParanoidiQ9WUN2.
KOiK05410.
OMAiFRGRHKK.
OrthoDBiEOG091G0354.
PhylomeDBiQ9WUN2.
TreeFamiTF324269.

Enzyme and pathway databases

ReactomeiR-MMU-1606341. IRF3 mediated activation of type 1 IFN.
R-MMU-3134975. Regulation of innate immune responses to cytosolic DNA.
R-MMU-3249367. STAT6-mediated induction of chemokines.
R-MMU-3270619. IRF3-mediated induction of type I IFN.
R-MMU-936440. Negative regulators of RIG-I/MDA5 signaling.

Miscellaneous databases

PROiQ9WUN2.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000020115.
CleanExiMM_TBK1.
ExpressionAtlasiQ9WUN2. baseline and differential.
GenevisibleiQ9WUN2. MM.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
[Graphical view]
PfamiPF00069. Pkinase. 1 hit.
[Graphical view]
SMARTiSM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiTBK1_MOUSE
AccessioniPrimary (citable) accession number: Q9WUN2
Secondary accession number(s): Q9CT90, Q9DC03
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 20, 2005
Last sequence update: November 1, 1999
Last modified: November 30, 2016
This is version 136 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  4. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.