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Q06187

- BTK_HUMAN

UniProt

Q06187 - BTK_HUMAN

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Protein

Tyrosine-protein kinase BTK

Gene
BTK, AGMX1, ATK, BPK
Organism
Homo sapiens (Human)
Status
Reviewed - 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.

Cofactori

Binds 1 zinc ion per subunit.

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.8 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei26 – 261Inositol-(1,3,4,5)-tetrakisphosphate
Binding sitei28 – 281Inositol-(1,3,4,5)-tetrakisphosphate
Binding sitei39 – 391Inositol-(1,3,4,5)-tetrakisphosphate
Binding sitei53 – 531Inositol-(1,3,4,5)-tetrakisphosphate; via carbonyl oxygen
Metal bindingi143 – 1431Zinc
Metal bindingi154 – 1541Zinc
Metal bindingi155 – 1551Zinc
Metal bindingi165 – 1651Zinc
Binding sitei430 – 4301ATP By similarity
Binding sitei445 – 4451Inhibitor
Binding sitei461 – 4611Inhibitor
Binding sitei477 – 4771Inhibitor
Active sitei521 – 5211Proton acceptor By similarity
Binding sitei538 – 5381Inhibitor
Binding sitei539 – 5391Inhibitor; via amide nitrogen
Binding sitei542 – 5421Inhibitor; via carbonyl oxygen

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri135 – 17137Btk-typeAdd
BLAST
Nucleotide bindingi408 – 4169ATP By similarity

GO - Molecular functioni

  1. ATP binding Source: HGNC
  2. identical protein binding Source: IntAct
  3. metal ion binding Source: UniProtKB-KW
  4. non-membrane spanning protein tyrosine kinase activity Source: UniProtKB
  5. phosphatidylinositol-3,4,5-trisphosphate binding Source: UniProtKB
  6. protein binding Source: UniProtKB
  7. protein tyrosine kinase activity Source: HGNC

GO - Biological processi

  1. adaptive immune response Source: UniProtKB
  2. apoptotic signaling pathway Source: ProtInc
  3. B cell activation Source: UniProtKB
  4. B cell receptor signaling pathway Source: UniProtKB
  5. calcium-mediated signaling Source: HGNC
  6. cell maturation Source: Ensembl
  7. Fc-epsilon receptor signaling pathway Source: Reactome
  8. histamine secretion by mast cell Source: Ensembl
  9. I-kappaB kinase/NF-kappaB signaling Source: Ensembl
  10. innate immune response Source: UniProtKB
  11. intracellular signal transduction Source: HGNC
  12. mesoderm development Source: ProtInc
  13. MyD88-dependent toll-like receptor signaling pathway Source: Reactome
  14. positive regulation of B cell differentiation Source: UniProtKB
  15. positive regulation of NF-kappaB transcription factor activity Source: UniProtKB
  16. protein autophosphorylation Source: Ensembl
  17. protein phosphorylation Source: HGNC
  18. regulation of B cell apoptotic process Source: UniProtKB
  19. regulation of B cell cytokine production Source: UniProtKB
  20. response to organic substance Source: Ensembl
  21. response to reactive oxygen species Source: Ensembl
  22. toll-like receptor 2 signaling pathway Source: Reactome
  23. toll-like receptor 4 signaling pathway Source: Reactome
  24. toll-like receptor signaling pathway Source: Reactome
  25. toll-like receptor TLR1:TLR2 signaling pathway Source: Reactome
  26. toll-like receptor TLR6:TLR2 signaling pathway Source: Reactome
  27. transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Kinase, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Adaptive immunity, Apoptosis, Immunity, Innate immunity, Transcription, Transcription regulation

Keywords - Ligandi

ATP-binding, Lipid-binding, Metal-binding, Nucleotide-binding, Zinc

Enzyme and pathway databases

BRENDAi2.7.10.2. 2681.
ReactomeiREACT_118700. Antigen activates B Cell Receptor (BCR) leading to generation of second messengers.
REACT_147814. DAP12 signaling.
REACT_160086. Regulation of actin dynamics for phagocytic cup formation.
REACT_163834. FCERI mediated Ca+2 mobilization.
REACT_6788. MyD88:Mal cascade initiated on plasma membrane.
SignaLinkiQ06187.

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
Gene namesi
Name:BTK
Synonyms:AGMX1, ATK, BPK
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome X

Organism-specific databases

HGNCiHGNC:1133. BTK.

Subcellular locationi

Cytoplasm. Cell membrane; Peripheral membrane protein. Nucleus
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 CRM1.4 Publications

GO - Cellular componenti

  1. cytoplasm Source: ProtInc
  2. cytoplasmic vesicle Source: Ensembl
  3. cytosol Source: UniProtKB
  4. intracellular membrane-bounded organelle Source: HPA
  5. mast cell granule Source: GOC
  6. membrane raft Source: HGNC
  7. nucleus Source: UniProtKB
  8. perinuclear region of cytoplasm Source: Ensembl
  9. plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Involvement in diseasei

X-linked agammaglobulinemia (XLA) [MIM:300755]: Humoral immunodeficiency disease which results in developmental defects in the maturation pathway of B-cells. Affected boys have normal levels of pre-B-cells in their bone marrow but virtually no circulating mature B-lymphocytes. This results in a lack of immunoglobulins of all classes and leads to recurrent bacterial infections like otitis, conjunctivitis, dermatitis, sinusitis in the first few years of life, or even some patients present overwhelming sepsis or meningitis, resulting in death in a few hours. Treatment in most cases is by infusion of intravenous immunoglobulin.
Note: The disease is caused by mutations affecting the gene represented in this entry.24 Publications
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti11 – 111L → P in XLA.
VAR_006216
Natural varianti12 – 121K → R in XLA. 1 Publication
VAR_006217
Natural varianti14 – 141S → F in XLA.
VAR_006218
Natural varianti19 – 191K → E in XLA. 1 Publication
VAR_008291
Natural varianti25 – 251F → S in XLA. 1 Publication
VAR_006219
Natural varianti27 – 271K → R in XLA.
VAR_008292
Natural varianti28 – 281R → C in XLA; no effect on phosphorylation of GTF2I.
VAR_008293
Natural varianti28 – 281R → H in XLA; moderate. 3 Publications
VAR_006220
Natural varianti28 – 281R → P in XLA. 1 Publication
VAR_006221
Natural varianti33 – 331T → P in XLA; severe. 2 Publications
VAR_006222
Natural varianti39 – 391Y → S in XLA. 1 Publication
VAR_008960
Natural varianti40 – 401Y → C in XLA.
VAR_008294
Natural varianti40 – 401Y → N in XLA.
VAR_008295
Natural varianti61 – 611I → N in XLA. 1 Publication
VAR_008296
Natural varianti64 – 641V → D in XLA.
VAR_008297
Natural varianti64 – 641V → F in XLA. 1 Publication
VAR_006223
Natural varianti103 – 1031Q → QSVFSSTR in XLA.
VAR_006224
Natural varianti113 – 1131V → D in XLA. 1 Publication
VAR_006225
Natural varianti115 – 1151S → F in XLA.
VAR_008298
Natural varianti117 – 1171T → P in XLA. 1 Publication
VAR_008299
Natural varianti127 – 1271Q → H in XLA. 1 Publication
VAR_008300
Natural varianti154 – 1541C → S in XLA. 1 Publication
VAR_008301
Natural varianti155 – 1551C → G in XLA.
VAR_008302
Natural varianti155 – 1551C → R in XLA. 2 Publications
VAR_008303
Natural varianti184 – 1841T → P in XLA.
VAR_008304
Natural varianti260 – 28021Missing in XLA; severe.
VAR_006226Add
BLAST
Natural varianti288 – 2881R → Q in XLA. 1 Publication
VAR_008305
Natural varianti288 – 2881R → W in XLA. 4 Publications
VAR_006227
Natural varianti295 – 2951L → P in XLA. 2 Publications
VAR_006228
Natural varianti302 – 3021G → E in XLA. 2 Publications
VAR_006230
Natural varianti302 – 3021G → R in XLA.
VAR_008306
Natural varianti302 – 3021Missing in XLA. 1 Publication
VAR_006229
Natural varianti307 – 3071R → G in XLA; loss of activity. 1 Publication
VAR_006231
Natural varianti307 – 3071R → T in XLA. 1 Publication
VAR_008307
Natural varianti308 – 3081D → E in XLA.
VAR_008308
Natural varianti319 – 3191V → A in XLA; moderate.
VAR_008309
Natural varianti334 – 3341Y → S in XLA. 1 Publication
VAR_006232
Natural varianti358 – 3581L → F in XLA. 1 Publication
VAR_006233
Natural varianti361 – 3611Y → C in XLA; mild. 1 Publication
Corresponds to variant rs28935478 [ dbSNP | Ensembl ].
VAR_006234
Natural varianti362 – 3621H → Q in XLA.
VAR_006235
Natural varianti364 – 3641H → P in XLA.
VAR_006236
Natural varianti365 – 3651N → Y in XLA.
VAR_006237
Natural varianti366 – 3661S → F in XLA.
VAR_008310
Natural varianti369 – 3691L → F in XLA. 1 Publication
VAR_008311
Natural varianti370 – 3701I → M in XLA. 1 Publication
VAR_006238
Natural varianti372 – 3721R → G in XLA. 1 Publication
VAR_008312
Natural varianti408 – 4081L → P in XLA; moderate. 1 Publication
VAR_006239
Natural varianti414 – 4141G → R in XLA. 1 Publication
VAR_008313
Natural varianti418 – 4181Y → H in XLA.
VAR_006240
Natural varianti429 – 4291I → N in XLA. 1 Publication
VAR_006241
Natural varianti430 – 4301K → E in XLA; loss of phosphorylation of GTF2I. 1 Publication
VAR_006242
Natural varianti430 – 4301K → R in XLA. 1 Publication
VAR_008314
Natural varianti445 – 4451E → D in XLA. 1 Publication
VAR_008315
Natural varianti462 – 4621G → D in XLA.
VAR_008316
Natural varianti462 – 4621G → V in XLA.
VAR_008317
Natural varianti476 – 4761Y → D in XLA. 1 Publication
VAR_006243
Natural varianti477 – 4771M → R in XLA. 1 Publication
VAR_006244
Natural varianti502 – 5021C → F in XLA.
VAR_006245
Natural varianti502 – 5021C → W in XLA. 1 Publication
VAR_006246
Natural varianti506 – 5061C → R in XLA. 1 Publication
VAR_006247
Natural varianti506 – 5061C → Y in XLA. 1 Publication
VAR_006248
Natural varianti508 – 5081A → D in XLA.
VAR_008318
Natural varianti509 – 5091M → I in XLA.
VAR_008319
Natural varianti509 – 5091M → V in XLA. 1 Publication
VAR_006249
Natural varianti512 – 5121L → P in XLA. 1 Publication
VAR_008961
Natural varianti512 – 5121L → Q in XLA. 1 Publication
VAR_008962
Natural varianti518 – 5181L → R in XLA.
VAR_008320
Natural varianti520 – 5201R → Q in XLA; severe; prevents activation due to absence of contact between the catalytic loop and the regulatory phosphorylated residue. 4 Publications
VAR_006251
Natural varianti521 – 5211D → G in XLA. 1 Publication
VAR_008321
Natural varianti521 – 5211D → H in XLA; severe. 1 Publication
VAR_006252
Natural varianti521 – 5211D → N in XLA; severe.
VAR_006253
Natural varianti523 – 5231A → E in XLA.
VAR_008322
Natural varianti525 – 5251R → G in XLA. 1 Publication
VAR_008323
Natural varianti525 – 5251R → P in XLA. 1 Publication
VAR_006254
Natural varianti525 – 5251R → Q in XLA; severe; disturbs ATP-binding. 2 Publications
VAR_006255
Natural varianti526 – 5261N → K in XLA. 1 Publication
VAR_006256
Natural varianti535 – 5351V → F in XLA. 1 Publication
VAR_008324
Natural varianti542 – 5421L → P in XLA; growth hormone deficiency. 1 Publication
VAR_006257
Natural varianti544 – 5441R → G in XLA. 1 Publication
VAR_008963
Natural varianti544 – 5441R → K in XLA. 1 Publication
VAR_006258
Natural varianti559 – 5591F → S in XLA. 1 Publication
VAR_008325
Natural varianti562 – 5621R → P in XLA. 2 Publications
Corresponds to variant rs28935176 [ dbSNP | Ensembl ].
VAR_006259
Natural varianti562 – 5621R → W in XLA. 4 Publications
VAR_006260
Natural varianti563 – 5631W → L in XLA. 1 Publication
VAR_008326
Natural varianti567 – 5671E → K in XLA; severe. 1 Publication
VAR_006261
Natural varianti578 – 5781S → Y in XLA. 1 Publication
VAR_008964
Natural varianti581 – 5811W → R in XLA.
VAR_006262
Natural varianti582 – 5821A → V in XLA. 2 Publications
VAR_006263
Natural varianti583 – 5831F → S in XLA.
VAR_008327
Natural varianti587 – 5871M → L in XLA; mild. 1 Publication
VAR_006264
Natural varianti589 – 5891E → D in XLA.
VAR_008328
Natural varianti589 – 5891E → G in XLA; moderate; interferes with substrate binding. 2 Publications
VAR_006265
Natural varianti589 – 5891E → K in XLA. 1 Publication
VAR_008965
Natural varianti592 – 5921S → P in XLA. 1 Publication
VAR_006267
Natural varianti594 – 5941G → E in XLA; mild; interferes with substrate binding. 2 Publications
VAR_006268
Natural varianti594 – 5941G → R in XLA. 1 Publication
VAR_006269
Natural varianti598 – 5981Y → C in XLA.
VAR_006270
Natural varianti607 – 6071A → D in XLA; mild. 1 Publication
VAR_006271
Natural varianti613 – 6131G → D in XLA; mild; interferes with substrate binding and/or domain interactions. 2 Publications
VAR_006272
Natural varianti619 – 6191P → A in XLA.
VAR_008330
Natural varianti619 – 6191P → S in XLA.
VAR_006273
Natural varianti619 – 6191P → T in XLA. 1 Publication
VAR_008331
Natural varianti622 – 6221A → P in XLA. 1 Publication
VAR_008332
Natural varianti626 – 6261V → G in XLA. 1 Publication
VAR_008333
Natural varianti630 – 6301M → K in XLA. 2 Publications
VAR_006275
Natural varianti630 – 6301M → T in XLA.
VAR_008334
Natural varianti633 – 6331C → Y in XLA. 1 Publication
VAR_006276
Natural varianti641 – 6411R → C in XLA. 1 Publication
VAR_006277
Natural varianti641 – 6411R → H in XLA; severe. 2 Publications
VAR_006278
Natural varianti644 – 6441F → L in XLA.
VAR_008335
Natural varianti644 – 6441F → S in XLA. 1 Publication
VAR_006279
Natural varianti647 – 6471L → P in XLA.
VAR_006280
Natural varianti652 – 6521L → P in XLA. 1 Publication
VAR_006281
X-linked hypogammaglobulinemia and isolated growth hormone deficiency (XLA-IGHD) [MIM:307200]: In rare cases XLA is inherited together with isolated growth hormone deficiency (IGHD).
Note: The disease may be caused by mutations affecting the gene represented in this entry.1 Publication

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi41 – 411E → K: No effect on phosphorylation of GTF2I. 2 Publications
Mutagenesisi189 – 1891P → A: No effect on phosphorylation of GTF2I. 2 Publications
Mutagenesisi223 – 2231Y → F: Loss of phosphorylation of GTF2I. 3 Publications
Mutagenesisi251 – 2522WW → LL: Large decrease in binding by SH3BP5. 2 Publications
Mutagenesisi251 – 2511W → L: No effect on phosphorylation of GTF2I. 2 Publications
Mutagenesisi307 – 3071R → K: Loss of phosphorylation of GTF2I. 2 Publications
Mutagenesisi551 – 5511Y → F: Loss of phosphorylation of GTF2I. 2 Publications
Mutagenesisi617 – 6171Y → E: Defective in mediating calcium response. 2 Publications

Keywords - Diseasei

Disease mutation

Organism-specific databases

MIMi300755. phenotype.
307200. phenotype.
Orphaneti632. Short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia.
47. X-linked agammaglobulinemia.
PharmGKBiPA25454.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Initiator methioninei1 – 11Removed1 Publication
Chaini2 – 659658Tyrosine-protein kinase BTKPRO_0000088065Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei2 – 21N-acetylalanine1 Publication
Modified residuei21 – 211Phosphoserine1 Publication
Modified residuei40 – 401Phosphotyrosine By similarity
Modified residuei55 – 551Phosphoserine1 Publication
Modified residuei115 – 1151Phosphoserine1 Publication
Modified residuei180 – 1801Phosphoserine; by PKC/PRKCB1 Publication
Modified residuei191 – 1911Phosphothreonine1 Publication
Modified residuei223 – 2231Phosphotyrosine; by autocatalysis4 Publications
Modified residuei344 – 3441Phosphotyrosine By similarity
Modified residuei361 – 3611Phosphotyrosine1 Publication
Modified residuei551 – 5511Phosphotyrosine; by LYN and SYK2 Publications
Modified residuei617 – 6171Phosphotyrosine1 Publication
Modified residuei623 – 6231Phosphoserine1 Publication
Modified residuei659 – 6591Phosphoserine1 Publication

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.7 Publications

Keywords - PTMi

Acetylation, Phosphoprotein

Proteomic databases

MaxQBiQ06187.
PaxDbiQ06187.
PRIDEiQ06187.

PTM databases

PhosphoSiteiQ06187.

Expressioni

Tissue specificityi

Predominantly expressed in B-lymphocytes.

Gene expression databases

ArrayExpressiQ06187.
BgeeiQ06187.
CleanExiHS_BTK.
GenevestigatoriQ06187.

Organism-specific databases

HPAiCAB016689.
HPA001198.
HPA002028.

Interactioni

Subunit structurei

Binds GTF2I through the PH domain. Interacts with SH3BP5 via the SH3 domain. Interacts with IBTK via its PH domain. Interacts with ARID3A, CAV1, FASLG, PIN1, TLR8 and TLR9.8 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself2EBI-624835,EBI-624835
ARID3AQ998563EBI-624835,EBI-5458244
BLNKQ8WV282EBI-624835,EBI-2623522
GTF2IP783476EBI-624835,EBI-359622
HSP90AB1P082382EBI-624835,EBI-352572
MALP211455EBI-624835,EBI-3932027
PRKCQQ047592EBI-624835,EBI-374762
SH3BP5O602394EBI-624835,EBI-624860

Protein-protein interaction databases

BioGridi107160. 69 interactions.
DIPiDIP-34071N.
IntActiQ06187. 44 interactions.
MINTiMINT-110243.
STRINGi9606.ENSP00000308176.

Structurei

Secondary structure

1
659
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi6 – 138
Beta strandi18 – 203
Beta strandi25 – 328
Beta strandi34 – 4310
Turni44 – 474
Beta strandi48 – 5710
Helixi58 – 603
Beta strandi61 – 666
Helixi75 – 773
Helixi93 – 964
Beta strandi100 – 1067
Beta strandi111 – 1166
Helixi118 – 13215
Beta strandi140 – 1423
Beta strandi149 – 1524
Turni153 – 1553
Beta strandi165 – 1673
Turni212 – 2154
Beta strandi218 – 2236
Beta strandi228 – 2325
Beta strandi240 – 2423
Beta strandi248 – 2525
Turni257 – 2593
Beta strandi261 – 2655
Turni266 – 2683
Beta strandi279 – 2824
Helixi288 – 29811
Beta strandi303 – 3086
Beta strandi310 – 3123
Beta strandi315 – 32612
Beta strandi330 – 3356
Beta strandi337 – 3393
Turni340 – 3423
Beta strandi343 – 3475
Beta strandi350 – 3545
Helixi355 – 3639
Beta strandi373 – 3764
Helixi393 – 3953
Helixi399 – 4013
Beta strandi402 – 41110
Beta strandi414 – 4218
Turni422 – 4243
Beta strandi425 – 4317
Helixi439 – 44911
Beta strandi460 – 4645
Beta strandi466 – 4694
Beta strandi471 – 4755
Helixi482 – 4876
Helixi489 – 4913
Helixi495 – 51420
Helixi524 – 5263
Beta strandi527 – 5293
Beta strandi535 – 5373
Helixi542 – 5454
Helixi549 – 5524
Turni554 – 5563
Helixi561 – 5633
Helixi566 – 5716
Helixi576 – 59116
Turni592 – 5943
Turni597 – 6004
Helixi603 – 6119
Helixi624 – 6329
Helixi638 – 6403
Helixi644 – 65714

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
1AWWNMR-A212-275[»]
1AWXNMR-A212-275[»]
1B55X-ray2.40A/B2-170[»]
1BTKX-ray1.60A/B2-170[»]
1BWNX-ray2.10A/B2-170[»]
1K2PX-ray2.10A/B397-659[»]
1QLYNMR-A216-273[»]
2GE9NMR-A270-387[»]
2Z0PX-ray2.58A/B/C/D2-170[»]
3GENX-ray1.60A382-659[»]
3K54X-ray1.94A382-659[»]
3OCSX-ray1.80A393-656[»]
3OCTX-ray1.95A393-656[»]
3P08X-ray2.30A/B393-659[»]
3PIXX-ray1.85A387-659[»]
3PIYX-ray2.55A387-659[»]
3PIZX-ray2.21A387-659[»]
3PJ1X-ray2.00A387-659[»]
3PJ2X-ray1.75A387-659[»]
3PJ3X-ray1.85A387-659[»]
4NWMX-ray2.03A/B396-657[»]
4OT5X-ray1.55A378-659[»]
4OT6X-ray2.05A378-659[»]
4OTQX-ray1.55A378-659[»]
4OTRX-ray1.95A378-659[»]
ProteinModelPortaliQ06187.
SMRiQ06187. Positions 2-170, 216-387, 395-657.

Miscellaneous databases

EvolutionaryTraceiQ06187.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini3 – 133131PHAdd
BLAST
Domaini214 – 27461SH3Add
BLAST
Domaini281 – 37797SH2Add
BLAST
Domaini402 – 655254Protein kinaseAdd
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni12 – 2413Inositol-(1,3,4,5)-tetrakisphosphate 1-bindingAdd
BLAST
Regioni474 – 4796Inhibitor-binding

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi581 – 5888CAV1-binding

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.4 Publications

Sequence similaritiesi

Contains 1 PH domain.
Contains 1 SH2 domain.
Contains 1 SH3 domain.

Keywords - Domaini

SH2 domain, SH3 domain, Zinc-finger

Phylogenomic databases

eggNOGiCOG0515.
HOGENOMiHOG000233859.
HOVERGENiHBG008761.
InParanoidiQ06187.
KOiK07370.
OMAiSCRHYNI.
PhylomeDBiQ06187.
TreeFamiTF351634.

Family and domain databases

Gene3Di2.30.29.30. 1 hit.
3.30.505.10. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR001849. PH_domain.
IPR011993. PH_like_dom.
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.
[Graphical view]
PfamiPF00779. BTK. 1 hit.
PF00169. PH. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]
PRINTSiPR00401. SH2DOMAIN.
PR00452. SH3DOMAIN.
PR00402. TECBTKDOMAIN.
PR00109. TYRKINASE.
SMARTiSM00107. BTK. 1 hit.
SM00233. PH. 1 hit.
SM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF50044. SSF50044. 1 hit.
SSF55550. SSF55550. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS50003. 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.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

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

This entry describes 2 isoformsi produced by alternative promoter usage. Align

Isoform BTK-A (identifier: Q06187-1) [UniParc]FASTAAdd to Basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

MAAVILESIF LKRSQQKKKT SPLNFKKRLF LLTVHKLSYY EYDFERGRRG    50
SKKGSIDVEK ITCVETVVPE KNPPPERQIP RRGEESSEME QISIIERFPY 100
PFQVVYDEGP LYVFSPTEEL RKRWIHQLKN VIRYNSDLVQ KYHPCFWIDG 150
QYLCCSQTAK NAMGCQILEN RNGSLKPGSS HRKTKKPLPP TPEEDQILKK 200
PLPPEPAAAP VSTSELKKVV ALYDYMPMNA NDLQLRKGDE YFILEESNLP 250
WWRARDKNGQ EGYIPSNYVT EAEDSIEMYE WYSKHMTRSQ AEQLLKQEGK 300
EGGFIVRDSS KAGKYTVSVF AKSTGDPQGV IRHYVVCSTP QSQYYLAEKH 350
LFSTIPELIN YHQHNSAGLI SRLKYPVSQQ NKNAPSTAGL GYGSWEIDPK 400
DLTFLKELGT GQFGVVKYGK WRGQYDVAIK MIKEGSMSED EFIEEAKVMM 450
NLSHEKLVQL YGVCTKQRPI FIITEYMANG CLLNYLREMR HRFQTQQLLE 500
MCKDVCEAME YLESKQFLHR DLAARNCLVN DQGVVKVSDF GLSRYVLDDE 550
YTSSVGSKFP VRWSPPEVLM YSKFSSKSDI WAFGVLMWEI YSLGKMPYER 600
FTNSETAEHI AQGLRLYRPH LASEKVYTIM YSCWHEKADE RPTFKILLSN 650
ILDVMDEES 659
Length:659
Mass (Da):76,281
Last modified:January 23, 2007 - v3
Checksum:iDF06B5D1FEC257CC
GO
Isoform BTK-C (identifier: Q06187-2) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MASWSIQQMVIGCPLCGRHCSGGEHTGELQKEEAM

Note: Produced by alternative promoter usage. Predominant form in many tumor cells where it may function as an anti-apoptotic cell survival factor.

Show »
Length:693
Mass (Da):79,937
Checksum:i8C582E0CD4D6280F
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti11 – 111L → P in XLA.
VAR_006216
Natural varianti12 – 121K → R in XLA. 1 Publication
VAR_006217
Natural varianti14 – 141S → F in XLA.
VAR_006218
Natural varianti19 – 191K → E in XLA. 1 Publication
VAR_008291
Natural varianti25 – 251F → S in XLA. 1 Publication
VAR_006219
Natural varianti27 – 271K → R in XLA.
VAR_008292
Natural varianti28 – 281R → C in XLA; no effect on phosphorylation of GTF2I.
VAR_008293
Natural varianti28 – 281R → H in XLA; moderate. 3 Publications
VAR_006220
Natural varianti28 – 281R → P in XLA. 1 Publication
VAR_006221
Natural varianti33 – 331T → P in XLA; severe. 2 Publications
VAR_006222
Natural varianti39 – 391Y → S in XLA. 1 Publication
VAR_008960
Natural varianti40 – 401Y → C in XLA.
VAR_008294
Natural varianti40 – 401Y → N in XLA.
VAR_008295
Natural varianti61 – 611I → N in XLA. 1 Publication
VAR_008296
Natural varianti64 – 641V → D in XLA.
VAR_008297
Natural varianti64 – 641V → F in XLA. 1 Publication
VAR_006223
Natural varianti82 – 821R → K.1 Publication
Corresponds to variant rs56035945 [ dbSNP | Ensembl ].
VAR_041676
Natural varianti103 – 1031Q → QSVFSSTR in XLA.
VAR_006224
Natural varianti113 – 1131V → D in XLA. 1 Publication
VAR_006225
Natural varianti115 – 1151S → F in XLA.
VAR_008298
Natural varianti117 – 1171T → P in XLA. 1 Publication
VAR_008299
Natural varianti127 – 1271Q → H in XLA. 1 Publication
VAR_008300
Natural varianti154 – 1541C → S in XLA. 1 Publication
VAR_008301
Natural varianti155 – 1551C → G in XLA.
VAR_008302
Natural varianti155 – 1551C → R in XLA. 2 Publications
VAR_008303
Natural varianti184 – 1841T → P in XLA.
VAR_008304
Natural varianti190 – 1901P → K in a lung large cell carcinoma sample; somatic mutation; requires 2 nucleotide substitutions. 1 Publication
VAR_041677
Natural varianti260 – 28021Missing in XLA; severe.
VAR_006226Add
BLAST
Natural varianti288 – 2881R → Q in XLA. 1 Publication
VAR_008305
Natural varianti288 – 2881R → W in XLA. 4 Publications
VAR_006227
Natural varianti295 – 2951L → P in XLA. 2 Publications
VAR_006228
Natural varianti302 – 3021G → E in XLA. 2 Publications
VAR_006230
Natural varianti302 – 3021G → R in XLA.
VAR_008306
Natural varianti302 – 3021Missing in XLA. 1 Publication
VAR_006229
Natural varianti307 – 3071R → G in XLA; loss of activity. 1 Publication
VAR_006231
Natural varianti307 – 3071R → T in XLA. 1 Publication
VAR_008307
Natural varianti308 – 3081D → E in XLA.
VAR_008308
Natural varianti319 – 3191V → A in XLA; moderate.
VAR_008309
Natural varianti334 – 3341Y → S in XLA. 1 Publication
VAR_006232
Natural varianti358 – 3581L → F in XLA. 1 Publication
VAR_006233
Natural varianti361 – 3611Y → C in XLA; mild. 1 Publication
Corresponds to variant rs28935478 [ dbSNP | Ensembl ].
VAR_006234
Natural varianti362 – 3621H → Q in XLA.
VAR_006235
Natural varianti364 – 3641H → P in XLA.
VAR_006236
Natural varianti365 – 3651N → Y in XLA.
VAR_006237
Natural varianti366 – 3661S → F in XLA.
VAR_008310
Natural varianti369 – 3691L → F in XLA. 1 Publication
VAR_008311
Natural varianti370 – 3701I → M in XLA. 1 Publication
VAR_006238
Natural varianti372 – 3721R → G in XLA. 1 Publication
VAR_008312
Natural varianti408 – 4081L → P in XLA; moderate. 1 Publication
VAR_006239
Natural varianti414 – 4141G → R in XLA. 1 Publication
VAR_008313
Natural varianti418 – 4181Y → H in XLA.
VAR_006240
Natural varianti429 – 4291I → N in XLA. 1 Publication
VAR_006241
Natural varianti430 – 4301K → E in XLA; loss of phosphorylation of GTF2I. 1 Publication
VAR_006242
Natural varianti430 – 4301K → R in XLA. 1 Publication
VAR_008314
Natural varianti445 – 4451E → D in XLA. 1 Publication
VAR_008315
Natural varianti462 – 4621G → D in XLA.
VAR_008316
Natural varianti462 – 4621G → V in XLA.
VAR_008317
Natural varianti476 – 4761Y → D in XLA. 1 Publication
VAR_006243
Natural varianti477 – 4771M → R in XLA. 1 Publication
VAR_006244
Natural varianti502 – 5021C → F in XLA.
VAR_006245
Natural varianti502 – 5021C → W in XLA. 1 Publication
VAR_006246
Natural varianti506 – 5061C → R in XLA. 1 Publication
VAR_006247
Natural varianti506 – 5061C → Y in XLA. 1 Publication
VAR_006248
Natural varianti508 – 5081A → D in XLA.
VAR_008318
Natural varianti509 – 5091M → I in XLA.
VAR_008319
Natural varianti509 – 5091M → V in XLA. 1 Publication
VAR_006249
Natural varianti512 – 5121L → P in XLA. 1 Publication
VAR_008961
Natural varianti512 – 5121L → Q in XLA. 1 Publication
VAR_008962
Natural varianti518 – 5181L → R in XLA.
VAR_008320
Natural varianti520 – 5201R → Q in XLA; severe; prevents activation due to absence of contact between the catalytic loop and the regulatory phosphorylated residue. 4 Publications
VAR_006251
Natural varianti521 – 5211D → G in XLA. 1 Publication
VAR_008321
Natural varianti521 – 5211D → H in XLA; severe. 1 Publication
VAR_006252
Natural varianti521 – 5211D → N in XLA; severe.
VAR_006253
Natural varianti523 – 5231A → E in XLA.
VAR_008322
Natural varianti525 – 5251R → G in XLA. 1 Publication
VAR_008323
Natural varianti525 – 5251R → P in XLA. 1 Publication
VAR_006254
Natural varianti525 – 5251R → Q in XLA; severe; disturbs ATP-binding. 2 Publications
VAR_006255
Natural varianti526 – 5261N → K in XLA. 1 Publication
VAR_006256
Natural varianti535 – 5351V → F in XLA. 1 Publication
VAR_008324
Natural varianti542 – 5421L → P in XLA; growth hormone deficiency. 1 Publication
VAR_006257
Natural varianti544 – 5441R → G in XLA. 1 Publication
VAR_008963
Natural varianti544 – 5441R → K in XLA. 1 Publication
VAR_006258
Natural varianti559 – 5591F → S in XLA. 1 Publication
VAR_008325
Natural varianti562 – 5621R → P in XLA. 2 Publications
Corresponds to variant rs28935176 [ dbSNP | Ensembl ].
VAR_006259
Natural varianti562 – 5621R → W in XLA. 4 Publications
VAR_006260
Natural varianti563 – 5631W → L in XLA. 1 Publication
VAR_008326
Natural varianti567 – 5671E → K in XLA; severe. 1 Publication
VAR_006261
Natural varianti578 – 5781S → Y in XLA. 1 Publication
VAR_008964
Natural varianti581 – 5811W → R in XLA.
VAR_006262
Natural varianti582 – 5821A → V in XLA. 2 Publications
VAR_006263
Natural varianti583 – 5831F → S in XLA.
VAR_008327
Natural varianti587 – 5871M → L in XLA; mild. 1 Publication
VAR_006264
Natural varianti589 – 5891E → D in XLA.
VAR_008328
Natural varianti589 – 5891E → G in XLA; moderate; interferes with substrate binding. 2 Publications
VAR_006265
Natural varianti589 – 5891E → K in XLA. 1 Publication
VAR_008965
Natural varianti592 – 5921S → P in XLA. 1 Publication
VAR_006267
Natural varianti594 – 5941G → E in XLA; mild; interferes with substrate binding. 2 Publications
VAR_006268
Natural varianti594 – 5941G → R in XLA. 1 Publication
VAR_006269
Natural varianti598 – 5981Y → C in XLA.
VAR_006270
Natural varianti607 – 6071A → D in XLA; mild. 1 Publication
VAR_006271
Natural varianti613 – 6131G → D in XLA; mild; interferes with substrate binding and/or domain interactions. 2 Publications
VAR_006272
Natural varianti619 – 6191P → A in XLA.
VAR_008330
Natural varianti619 – 6191P → S in XLA.
VAR_006273
Natural varianti619 – 6191P → T in XLA. 1 Publication
VAR_008331
Natural varianti622 – 6221A → P in XLA. 1 Publication
VAR_008332
Natural varianti626 – 6261V → G in XLA. 1 Publication
VAR_008333
Natural varianti630 – 6301M → I Polymorphism, 35%.
VAR_006274
Natural varianti630 – 6301M → K in XLA. 2 Publications