Q9WUN2 (TBK1_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine/threonine-protein kinase TBK1
EC=2.7.11.1

Alternative name(s):
T2K
TANK-binding kinase 1

Gene names

Name:

Tbk1

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	729 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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 IFN-alpha and IFN-beta. 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 or SINTBAD can be recruited to the TBK1-containing-complexes. Under particular conditions, functions as a NF-kappa-B effector by phosphorylating IKKA/CHUK 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. Attenuates retroviral budding by phosphorylating the endosomal sorting complex required for transport-I (ESCRT-I) subunit VPS37C. Phosphorylates and activates AKT1 By similarity. Ref.1 Ref.6
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Subunit structure	Self-associates. Interacts with TIRAP, TANK and TRAF2. Part of a ternary complex consisting of TANK, TRAF2 and TBK1. Interacts with AZI2; this interaction mediates 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 TICAM1/TRIF, IRF3 and DDX58/RIG-I. Interacts with OPTN and TRAF3. Interacts with SRC. Interacts with the exocyst complex subunit SEC5/EXOC2; this interaction is sufficient to trigger TBK1 activity By similarity. Interacts with TMEM173/MITA By similarity. Interacts with IFIT3 (via N-terminus) By similarity. Interacts with MAVS only in the presence of IFIT3 By similarity.
Subcellular location	Cytoplasm. Note: Upon mitogen stimulation or triggering of the immune system, TBK1 is recruited to the exocyst by EXOC2 By similarity.
Domain	Comprises A N-terminal kinase domain, an ubiquitin-like domain and a C-terminal leucine-zipper By similarity.
Post-translational modification	Autophosphorylation at Ser-172 activates the kinase, and is an essential step for virus-triggered signaling. Phosphorylated by IKBKB/IKKB at Ser-172 By similarity. 'Lys-63'-linked polyubiquitination by MIB1 after RNA virus infection, or by NRDP1 after LPS stimulation, may participate in kinase activation. 'Lys-48'-linked polyubiquitination at Lys-670 by DTX4 leads to proteasomal degradation By similarity.
Disruption phenotype	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. Ref.4 Ref.5
Sequence similarities	Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. I-kappa-B kinase subfamily. Contains 1 protein kinase domain. Contains 1 ubiquitin-like domain.

Ontologies

Keywords
Biological process	Antiviral defense Immunity Innate immunity
Cellular component	Cytoplasm
Domain	Coiled coil
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Isopeptide bond Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of innate immune response Inferred from mutant phenotype Ref.6. Source: MGI defense response to Gram-positive bacterium Inferred from mutant phenotype Ref.6. Source: MGI defense response to virus Inferred from electronic annotation. Source: UniProtKB-KW innate immune response Inferred from electronic annotation. Source: UniProtKB-KW negative regulation of gene expression Inferred from mutant phenotype PubMed 18665841. Source: UniProtKB positive regulation of I-kappaB kinase/NF-kappaB cascade Inferred from electronic annotation. Source: Compara positive regulation of interferon-alpha production Inferred from electronic annotation. Source: Compara positive regulation of interferon-beta biosynthetic process Inferred from mutant phenotype Ref.6. Source: MGI positive regulation of interferon-beta production Inferred from electronic annotation. Source: Compara positive regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara
Cellular_component	cytosol Traceable author statement. Source: Reactome
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW nucleic acid binding Inferred from direct assay PubMed 19158679. Source: MGI protein serine/threonine kinase activity Inferred from electronic annotation. Source: UniProtKB-KW
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
Tank	P70347	4	EBI-764193,EBI-646116

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 729	729	Serine/threonine-protein kinase TBK1		PRO_0000086744
Regions
	Domain	9 – 310	302	Protein kinase
	Domain	309 – 385	77	Ubiquitin-like
	Nucleotide binding	15 – 23	9	ATP By similarity
	Coiled coil	626 – 713	88	Potential
Sites
	Active site	135	1	Proton acceptor By similarity
	Binding site	38	1	ATP By similarity
Amino acid modifications
	Modified residue	172	1	Phosphoserine; by autocatalysis and IKKB By similarity
	Cross-link	670		Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) By similarity
Experimental info
	Sequence conflict	468	1	L → V in BAB23440. Ref.3
	Sequence conflict	594	1	A → S in BAB23244. Ref.3
	Sequence conflict	631	1	L → S in BAB23440. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q9WUN2 [UniParc]. Last modified November 1, 1999. Version 1. Checksum: 978ADDE3061DACD1	FASTA	729	83,425
	10 20 30 40 50 60 MQSTSNHLWL LSDILGQGAT ANVFRGRHKK TGDLYAVKVF NNISFLRPVD VQMREFEVLK 70 80 90 100 110 120 KLNHKNIVKL FAIEEETTTR HKVLIMEFCP CGSLYTVLEE PSNAYGLPES EFLIVLRDVV 130 140 150 160 170 180 GGMNHLRENG IVHRDIKPGN IMRVIGEDGQ SVYKLTDFGA ARELEDDEQF VSLYGTEEYL 190 200 210 220 230 240 HPDMYERAVL RKDHQKKYGA TVDLWSVGVT FYHAATGSLP FRPFEGPRRN KEVMYKIITG 250 260 270 280 290 300 KPSGAISGVQ KAENGPIDWS GDMPLSCSLS QGLQALLTPV LANILEADQE KCWGFDQFFA 310 320 330 340 350 360 ETSDVLHRMV IHVFSLQHMT AHKIYIHSYN TAAVFHELVY KQTKIVSSNQ ELIYEGRRLV 370 380 390 400 410 420 LELGRLAQHF PKTTEENPIF VTSREQLNTV GLRYEKISLP KIHPRYDLDG DASMAKAVTG 430 440 450 460 470 480 VVCYACRTAS TLLLYQELMR KGVRWLVELV KDDYNETVHK KTEVVITLDF CIRNIEKTVK 490 500 510 520 530 540 VYEKLMKVNL EAAELGEISD IHTKLLRLSS SQGTIESSLQ DISSRLSPGG LLADTWAHQE 550 560 570 580 590 600 GTHPRDRNVE KLQVLLNCIT EIYYQFKKDK AERRLAYNEE QIHKFDKQKL YYHATKAMSH 610 620 630 640 650 660 FSEECVRKYE AFKDKSEEWM RKMLHLRKQL LSLTNQCFDI EEEVSKYQDY TNELQETLPQ 670 680 690 700 710 720 KMLAASGGVK HAMAPIYPSS NTLVEMTLGM KKLKEEMEGV VKELAENNHI LERFGSLTMD GGLRNVDCL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"NF-kB activation by a signaling complex containing TRAF2, TANK, and TBK1, a novel IKK-related kinase." Pomerantz J.L., Baltimore D. EMBO J. 18:6694-6704(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION. Tissue: Spleen.
[2]	"Mus musculus homolog to human T2K cDNA." Wisniewski D., Marcy A.I. Submitted (APR-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Strain: Swiss Webster / NIH.
[3]	"The transcriptional landscape of the mammalian genome." Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J. , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y. Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6J. Tissue: Lung.
[4]	"Deficiency of T2K leads to apoptotic liver degeneration and impaired NF-kappaB-dependent gene transcription." Bonnard M., Mirtsos C., Suzuki S., Graham K., Huang J., Ng M., Itie A., Wakeham A., Shahinian A., Henzel W.J., Elia A.J., Shillinglaw W., Mak T.W., Cao Z., Yeh W.-C. EMBO J. 19:4976-4985(2000) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[5]	"IFN-regulatory factor 3-dependent gene expression is defective in Tbk1-deficient mouse embryonic fibroblasts." McWhirter S.M., Fitzgerald K.A., Rosains J., Rowe D.C., Golenbock D.T., Maniatis T. Proc. Natl. Acad. Sci. U.S.A. 101:233-238(2004) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE.
[6]	"Immune activation of type I IFNs by Listeria monocytogenes occurs independently of TLR4, TLR2, and receptor interacting protein 2 but involves TNFR-associated NF kappa B kinase-binding kinase 1." O'Connell R.M., Vaidya S.A., Perry A.K., Saha S.K., Dempsey P.W., Cheng G. J. Immunol. 174:1602-1607(2005) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF191839 mRNA. Translation: AAF05990.1. AF145705 mRNA. Translation: AAD34590.1. AK004269 mRNA. Translation: BAB23244.1. AK004649 mRNA. Translation: BAB23440.1.
IPI	IPI00124856.
RefSeq	NP_062760.3. NM_019786.4.
UniGene	Mm.34580.
3D structure databases
ProteinModelPortal	Q9WUN2.
SMR	Q9WUN2. Positions 2-385.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-29880N.
IntAct	Q9WUN2. 8 interactions.
MINT	MINT-111979.
PTM databases
PhosphoSite	Q9WUN2.
Proteomic databases
PaxDb	Q9WUN2.
PRIDE	Q9WUN2.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000020316; ENSMUSP00000020316; ENSMUSG00000020115.
GeneID	56480.
KEGG	mmu:56480.
UCSC	uc007hft.3. mouse.
Organism-specific databases
CTD	29110.
MGI	MGI:1929658. Tbk1.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00530000063051.
HOGENOM	HOG000220867.
HOVERGEN	HBG008494.
InParanoid	Q9WUN2.
KO	K05410.
OMA	LLYQELM.
OrthoDB	EOG4229J4.
Enzyme and pathway databases
Reactome	REACT_107772. Immune System.
Gene expression databases
ArrayExpress	Q9WUN2.
Bgee	Q9WUN2.
CleanEx	MM_TBK1.
Genevestigator	Q9WUN2.
GermOnline	ENSMUSG00000020115. Mus musculus.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. False negative. PS00299. UBIQUITIN_1. False negative. PS50053. UBIQUITIN_2. False negative. [Graphical view]
ProtoNet	Search...
Other
NextBio	312746.
SOURCE	Search...

Entry information

Entry name

TBK1_MOUSE

Accession

Primary (citable) accession number: Q9WUN2
Secondary accession number(s): Q9CT90, Q9DC03

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 20, 2005
Last sequence update:	November 1, 1999
Last modified:	May 29, 2013
This is version 101 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program