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UniProtKB - P35991 (BTK_MOUSE)

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Protein

Tyrosine-protein kinase BTK

Gene

Btk

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

Functioni

Non-receptor tyrosine kinase indispensable for B lymphocyte development, differentiation and signaling. Binding of antigen to the B-cell antigen receptor (BCR) triggers signaling that ultimately leads to B-cell activation. After BCR engagement and activation at the plasma membrane, phosphorylates PLCG2 at several sites, igniting the downstream signaling pathway through calcium mobilization, followed by activation of the protein kinase C (PKC) family members. PLCG2 phosphorylation is performed in close cooperation with the adapter protein B-cell linker protein BLNK. BTK acts as a platform to bring together a diverse array of signaling proteins and is implicated in cytokine receptor signaling pathways. Plays an important role in the function of immune cells of innate as well as adaptive immunity, as a component of the Toll-like receptors (TLR) pathway. The TLR pathway acts as a primary surveillance system for the detection of pathogens and are crucial to the activation of host defense. Especially, is a critical molecule in regulating TLR9 activation in splenic B-cells. Within the TLR pathway, induces tyrosine phosphorylation of TIRAP which leads to TIRAP degradation. BTK plays also a critical role in transcription regulation. Induces the activity of NF-kappa-B, which is involved in regulating the expression of hundreds of genes. BTK is involved on the signaling pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently phosphorylates transcription factor GTF2I on tyrosine residues in response to BCR. GTF2I then translocates to the nucleus to bind regulatory enhancer elements to modulate gene expression. ARID3A and NFAT are other transcriptional target of BTK. BTK is required for the formation of functional ARID3A DNA-binding complexes. There is however no evidence that BTK itself binds directly to DNA. BTK has a dual role in the regulation of apoptosis.6 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

Cofactori

Zn2+By similarityNote: Binds 1 zinc ion per subunit.By similarity

Enzyme regulationi

Activated by phosphorylation. In primary B lymphocytes, is almost always non-phosphorylated and is thus catalytically inactive. Stimulation of TLR8 and TLR9 causes BTK activation. As a negative feedback mechanism to fine-tune BCR signaling, activated PRKCB down-modulates BTK function via direct phosphorylation of BTK at Ser-180, resulting in translocation of BTK back to the cytoplasmic fraction. PIN1, SH3BP5, and IBTK were also identified as BTK activity inhibitors. Interaction with CAV1 leads to dramatic down-regulation of the kinase activity of BTK. LFM-13A is a specific inhibitor of BTK. Dasatinib, a cancer drug acting as a tyrosine kinase inhibitor, also blocks BTK activity.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei26Inositol-(1,3,4,5)-tetrakisphosphateBy similarity1
Binding sitei28Inositol-(1,3,4,5)-tetrakisphosphateBy similarity1
Binding sitei39Inositol-(1,3,4,5)-tetrakisphosphateBy similarity1
Binding sitei53Inositol-(1,3,4,5)-tetrakisphosphate; via carbonyl oxygenBy similarity1
Metal bindingi143ZincBy similarity1
Metal bindingi154ZincBy similarity1
Metal bindingi155ZincBy similarity1
Metal bindingi165ZincBy similarity1
Binding sitei430ATPPROSITE-ProRule annotation1
Binding sitei445InhibitorBy similarity1
Binding sitei461InhibitorBy similarity1
Binding sitei477InhibitorBy similarity1
Active sitei521Proton acceptorPROSITE-ProRule annotation1
Binding sitei538InhibitorBy similarity1
Binding sitei539Inhibitor; via amide nitrogenBy similarity1
Binding sitei542Inhibitor; via carbonyl oxygenBy similarity1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri135 – 171Btk-typePROSITE-ProRule annotationAdd BLAST37
Nucleotide bindingi408 – 416ATPPROSITE-ProRule annotation9

GO - Molecular functioni

Complete GO annotation...

GO - Biological processi

  • apoptotic process Source: UniProtKB-KW
  • B cell affinity maturation Source: MGI
  • cell maturation Source: MGI
  • cellular response to interleukin-7 Source: MGI
  • cellular response to molecule of fungal origin Source: Ensembl
  • cellular response to reactive oxygen species Source: Ensembl
  • Fc-epsilon receptor signaling pathway Source: Reactome
  • histamine secretion by mast cell Source: Ensembl
  • I-kappaB kinase/NF-kappaB signaling Source: MGI
  • innate immune response Source: GO_Central
  • negative regulation of B cell proliferation Source: MGI
  • negative regulation of cytokine production Source: CACAO
  • peptidyl-tyrosine autophosphorylation Source: GO_Central
  • peptidyl-tyrosine phosphorylation Source: MGI
  • positive regulation of type I hypersensitivity Source: Ensembl
  • positive regulation of type III hypersensitivity Source: Ensembl
  • protein phosphorylation Source: MGI
  • regulation of transcription, DNA-templated Source: UniProtKB-KW
  • transcription, DNA-templated Source: UniProtKB-KW
  • transmembrane receptor protein tyrosine kinase signaling pathway Source: GO_Central
Complete GO annotation...

Keywordsi

Molecular functionKinase, Transferase, Tyrosine-protein kinase
Biological processAdaptive immunity, Apoptosis, Immunity, Innate immunity, Transcription, Transcription regulation
LigandATP-binding, Lipid-binding, Metal-binding, Nucleotide-binding, Zinc

Enzyme and pathway databases

BRENDAi2.7.10.2. 3474.
ReactomeiR-MMU-2424491. DAP12 signaling.
R-MMU-2871809. FCERI mediated Ca+2 mobilization.
R-MMU-983695. Antigen activates B Cell Receptor (BCR) leading to generation of second messengers.

Names & Taxonomyi

Protein namesi
Recommended name:
Tyrosine-protein kinase BTK (EC:2.7.10.2)
Alternative name(s):
Agammaglobulinemia tyrosine kinase
Short name:
ATK
B-cell progenitor kinase
Short name:
BPK
Bruton tyrosine kinase
Kinase EMB
Gene namesi
Name:Btk
Synonyms:Bpk
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Mus › Mus
Proteomesi
  • UP000000589 Componenti: Chromosome X

Organism-specific databases

MGIiMGI:88216. Btk.

Subcellular locationi

  • Cytoplasm 1 Publication
  • Cell membrane 1 Publication; Peripheral membrane protein 1 Publication
  • Nucleus 1 Publication

    • Note: In steady state, BTK is predominantly cytosolic. Following B-cell receptor (BCR) engagement by antigen, translocates to the plasma membrane through its PH domain. Plasma membrane localization is a critical step in the activation of BTK. A fraction of BTK also shuttles between the nucleus and the cytoplasm, and nuclear export is mediated by the nuclear export receptor CRM1.By similarity

GO - Cellular componenti

  • cytoplasm Source: MGI
  • cytoplasmic vesicle Source: MGI
  • cytosol Source: MGI
  • extrinsic component of cytoplasmic side of plasma membrane Source: GO_Central
  • mast cell granule Source: GOC
  • membrane raft Source: MGI
  • nucleus Source: MGI
  • perinuclear region of cytoplasm Source: Ensembl
  • plasma membrane Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Involvement in diseasei

Defects in Btk are the cause of murine X-linked immunodeficiency (XID).

Disruption phenotypei

Prevents BCR-induced activation of NF-kappa-B.1 Publication

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi41E → K: Constitutive activation. 1 Publication1
Mutagenesisi223Y → F: No autophosphorylation. 1 Publication1
Mutagenesisi430K → R: Loss of activity and no phosphorylation. 2 Publications1

Keywords - Diseasei

Disease mutation

Chemistry databases

ChEMBLiCHEMBL3259478.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Initiator methionineiRemovedBy similarity
ChainiPRO_00000880662 – 659Tyrosine-protein kinase BTKAdd BLAST658

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei2N-acetylalanineBy similarity1
Modified residuei21PhosphoserineBy similarity1
Modified residuei40PhosphotyrosineCombined sources1
Modified residuei55PhosphoserineBy similarity1
Modified residuei115PhosphoserineBy similarity1
Modified residuei180Phosphoserine; by PKC/PRKCBBy similarity1
Modified residuei191PhosphothreonineBy similarity1
Modified residuei223Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei344PhosphotyrosineCombined sources1
Modified residuei361PhosphotyrosineBy similarity1
Modified residuei551Phosphotyrosine; by LYN and SYKCombined sources1 Publication1
Modified residuei604PhosphoserineBy similarity1
Modified residuei617PhosphotyrosineBy similarity1
Modified residuei623PhosphoserineBy similarity1
Modified residuei659PhosphoserineBy similarity1

Post-translational modificationi

Following B-cell receptor (BCR) engagement, translocates to the plasma membrane where it gets phosphorylated at Tyr-551 by LYN and SYK. Phosphorylation at Tyr-551 is followed by autophosphorylation of Tyr-223 which may create a docking site for a SH2 containing protein. Phosphorylation at Ser-180 by PRKCB, leads in translocation of BTK back to the cytoplasmic fraction. Phosphorylation at Ser-21 and Ser-115 creates a binding site for PIN1 at these Ser-Pro motifs, and promotes it's recruitment (By similarity).By similarity

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

MaxQBiP35991.
PaxDbiP35991.
PeptideAtlasiP35991.
PRIDEiP35991.

PTM databases

iPTMnetiP35991.
PhosphoSitePlusiP35991.

Expressioni

Gene expression databases

BgeeiENSMUSG00000031264.
CleanExiMM_BTK.
ExpressionAtlasiP35991. baseline and differential.
GenevisibleiP35991. MM.

Interactioni

Subunit structurei

Binds GTF2I through the PH domain. Interacts with SH3BP5 via the SH3 domain. Interacts with IBTK via its PH domain (By similarity). Interacts with ARID3A. Interacts with CAV1, FASLG, PIN1, TLR8 and TLR9 (By similarity).By similarity

Binary interactionsi

Show more details

GO - Molecular functioni

Complete GO annotation...

Protein-protein interaction databases

BioGridi198400. 6 interactors.
IntActiP35991. 29 interactors.
MINTiMINT-1549372.
STRINGi10090.ENSMUSP00000033617.

Chemistry databases

BindingDBiP35991.

Structurei

Secondary structure

1659
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi217 – 223Combined sources7
Beta strandi240 – 245Combined sources6
Beta strandi248 – 255Combined sources8
Beta strandi261 – 265Combined sources5
Beta strandi279 – 281Combined sources3
Helixi288 – 294Combined sources7
Beta strandi304 – 307Combined sources4
Beta strandi316 – 321Combined sources6
Beta strandi330 – 335Combined sources6
Helixi355 – 361Combined sources7
Turni362 – 364Combined sources3
Beta strandi369 – 371Combined sources3
Beta strandi388 – 391Combined sources4
Beta strandi401 – 407Combined sources7
Beta strandi412 – 414Combined sources3
Beta strandi416 – 421Combined sources6
Turni422 – 424Combined sources3
Beta strandi425 – 431Combined sources7
Helixi439 – 450Combined sources12
Beta strandi460 – 469Combined sources10
Beta strandi471 – 475Combined sources5
Helixi482 – 488Combined sources7
Helixi490 – 492Combined sources3
Helixi495 – 497Combined sources3
Helixi498 – 514Combined sources17
Helixi524 – 526Combined sources3
Beta strandi527 – 529Combined sources3
Beta strandi535 – 537Combined sources3
Helixi542 – 545Combined sources4
Helixi549 – 552Combined sources4
Helixi561 – 563Combined sources3
Helixi566 – 571Combined sources6
Helixi576 – 591Combined sources16
Turni592 – 594Combined sources3
Turni597 – 600Combined sources4
Helixi603 – 612Combined sources10
Helixi624 – 632Combined sources9
Helixi638 – 640Combined sources3
Helixi644 – 656Combined sources13

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4XI2X-ray2.60A214-659[»]
ProteinModelPortaliP35991.
SMRiP35991.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini3 – 133PHPROSITE-ProRule annotationAdd BLAST131
Domaini214 – 274SH3PROSITE-ProRule annotationAdd BLAST61
Domaini281 – 377SH2PROSITE-ProRule annotationAdd BLAST97
Domaini402 – 655Protein kinasePROSITE-ProRule annotationAdd BLAST254

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni12 – 24Inositol-(1,3,4,5)-tetrakisphosphate 1-bindingBy similarityAdd BLAST13
Regioni474 – 479Inhibitor-bindingBy similarity6

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi581 – 588CAV1-bindingBy similarity8

Domaini

The PH domain mediates the binding to inositol polyphosphate and phosphoinositides, leading to its targeting to the plasma membrane. It is extended in the BTK kinase family by a region designated the TH (Tec homology) domain, which consists of about 80 residues preceding the SH3 domain.1 Publication

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri135 – 171Btk-typePROSITE-ProRule annotationAdd BLAST37

Keywords - Domaini

SH2 domain, SH3 domain, Zinc-finger

Phylogenomic databases

eggNOGiKOG0197. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00760000119011.
HOGENOMiHOG000233859.
HOVERGENiHBG008761.
InParanoidiP35991.
KOiK07370.
OMAiKYGKWQG.
OrthoDBiEOG091G0D46.
PhylomeDBiP35991.
TreeFamiTF351634.

Family and domain databases

Gene3Di2.30.29.30. 1 hit.
3.30.505.10. 1 hit.
InterProiView protein in InterPro
IPR011009. Kinase-like_dom.
IPR011993. PH_dom-like.
IPR001849. PH_domain.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR000980. SH2.
IPR001452. SH3_domain.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR001562. Znf_Btk_motif.
PfamiView protein in Pfam
PF00779. BTK. 1 hit.
PF00169. PH. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
PRINTSiPR00401. SH2DOMAIN.
PR00452. SH3DOMAIN.
PR00402. TECBTKDOMAIN.
PR00109. TYRKINASE.
SMARTiView protein in SMART
SM00107. BTK. 1 hit.
SM00233. PH. 1 hit.
SM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
SUPFAMiSSF50044. SSF50044. 1 hit.
SSF50729. SSF50729. 1 hit.
SSF55550. SSF55550. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiView protein in PROSITE
PS50003. PH_DOMAIN. 1 hit.
PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
PS50001. SH2. 1 hit.
PS50002. SH3. 1 hit.
PS51113. ZF_BTK. 1 hit.

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

P35991-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAAVILESIF LKRSQQKKKT SPLNFKKRLF LLTVHKLSYY EYDFERGRRG 
        60         70         80         90        100
SKKGSIDVEK ITCVETVIPE KNPPPERQIP RRGEESSEME QISIIERFPY 
       110        120        130        140        150
PFQVVYDEGP LYVFSPTEEL RKRWIHQLKN VIRYNSDLVQ KYHPCFWIDG 
       160        170        180        190        200
QYLCCSQTAK NAMGCQILEN RNGSLKPGSS HRKTKKPLPP TPEEDQILKK 
       210        220        230        240        250
PLPPEPTAAP ISTTELKKVV ALYDYMPMNA NDLQLRKGEE YFILEESNLP 
       260        270        280        290        300
WWRARDKNGQ EGYIPSNYIT EAEDSIEMYE WYSKHMTRSQ AEQLLKQEGK 
       310        320        330        340        350
EGGFIVRDSS KAGKYTVSVF AKSTGEPQGV IRHYVVCSTP QSQYYLAEKH 
       360        370        380        390        400
LFSTIPELIN YHQHNSAGLI SRLKYPVSKQ NKNAPSTAGL GYGSWEIDPK 
       410        420        430        440        450
DLTFLKELGT GQFGVVKYGK WRGQYDVAIK MIREGSMSED EFIEEAKVMM 
       460        470        480        490        500
NLSHEKLVQL YGVCTKQRPI FIITEYMANG CLLNYLREMR HRFQTQQLLE 
       510        520        530        540        550
MCKDVCEAME YLESKQFLHR DLAARNCLVN DQGVVKVSDF GLSRYVLDDE 
       560        570        580        590        600
YTSSVGSKFP VRWSPPEVLM YSKFSSKSDI WAFGVLMWEI YSLGKMPYER 
       610        620        630        640        650
FTNSETAEHI AQGLRLYRPH LASERVYTIM YSCWHEKADE RPSFKILLSN 

ILDVMDEES
Length:659
Mass (Da):76,437
Last modified:January 23, 2007 - v4
Checksum:iE502B798BC36E223
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti67V → A in L10627 (PubMed:8476425).Curated1
Sequence conflicti123R → P in AAA37316 (PubMed:8425221).Curated1
Sequence conflicti197I → IWI (PubMed:8476425).Curated1
Sequence conflicti450Missing in L10627 (PubMed:8476425).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural varianti28R → C in XID; prevents interaction with ARID3A. 2 Publications1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L08967 mRNA. Translation: AAA37316.1.
L10627 mRNA. No translation available.
L29788 mRNA. Translation: AAA66943.1.
U58105 Genomic DNA. Translation: AAB47246.1.
CCDSiCCDS30396.1.
PIRiI49553.
RefSeqiNP_038510.2. NM_013482.2.
XP_006528546.1. XM_006528483.3.
XP_006528547.1. XM_006528484.3.
XP_006528548.1. XM_006528485.3.
UniGeneiMm.4475.

Genome annotation databases

EnsembliENSMUST00000033617; ENSMUSP00000033617; ENSMUSG00000031264.
GeneIDi12229.
KEGGimmu:12229.
UCSCiuc009uge.2. mouse.

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.

Entry informationi

Entry nameiBTK_MOUSE
AccessioniPrimary (citable) accession number: P35991
Secondary accession number(s): Q61365
Entry historyiIntegrated into UniProtKB/Swiss-Prot: June 1, 1994
Last sequence update: January 23, 2007
Last modified: June 7, 2017
This is version 179 of the entry and version 4 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, 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