Q06187 (BTK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	BTK
Synonyms:	AGMX1, ATK, BPK

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	659 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Ref.15 Ref.22 Ref.27 Ref.28 Ref.29 Ref.30
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Cofactor	Binds 1 zinc ion per subunit.
Enzyme regulation	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. Ref.14 Ref.18 Ref.21 Ref.23 Ref.24 Ref.26 Ref.29 Ref.30
Subunit structure	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. Ref.16 Ref.18 Ref.23 Ref.24 Ref.26 Ref.28 Ref.30 Ref.31
Subcellular location	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. Ref.17 Ref.19 Ref.20 Ref.24
Tissue specificity	Predominantly expressed in B-lymphocytes.
Domain	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. Ref.13 Ref.17 Ref.24 Ref.38
Post-translational modification	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. Ref.11 Ref.14 Ref.15 Ref.21 Ref.25 Ref.26 Ref.30
Involvement in disease	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. Ref.5 Ref.12 Ref.49 Ref.50 Ref.51 Ref.52 Ref.53 Ref.54 Ref.55 Ref.56 Ref.57 Ref.58 Ref.59 Ref.60 Ref.61 Ref.62 Ref.63 Ref.64 Ref.65 Ref.66 Ref.67 Ref.68 Ref.69 Ref.70 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. Ref.12
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. TEC subfamily. Contains 1 Btk-type zinc finger. Contains 1 PH domain. Contains 1 protein kinase domain. Contains 1 SH2 domain. Contains 1 SH3 domain.

Ontologies

Keywords
Biological process	Adaptive immunity Apoptosis Immunity Innate immunity Transcription Transcription regulation
Cellular component	Cell membrane Cytoplasm Membrane Nucleus
Coding sequence diversity	Polymorphism
Disease	Disease mutation
Domain	SH2 domain SH3 domain Zinc-finger
Ligand	ATP-binding Lipid-binding Metal-binding Nucleotide-binding Zinc
Molecular function	Kinase Transferase Tyrosine-protein kinase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	B cell activation Traceable author statement Ref.33. Source: UniProtKB B cell receptor signaling pathway Traceable author statement Ref.33. Source: UniProtKB I-kappaB kinase/NF-kappaB cascade Inferred from electronic annotation. Source: Compara MyD88-dependent toll-like receptor signaling pathway Traceable author statement. Source: Reactome Toll signaling pathway Traceable author statement. Source: Reactome adaptive immune response Traceable author statement Ref.33. Source: UniProtKB apoptotic signaling pathway Traceable author statement PubMed 8688094. Source: ProtInc calcium-mediated signaling Traceable author statement PubMed 15046600. Source: HGNC cell maturation Inferred from electronic annotation. Source: Compara innate immune response Traceable author statement Ref.33. Source: UniProtKB mesoderm development Traceable author statement Ref.12. Source: ProtInc peptidyl-tyrosine phosphorylation Inferred from electronic annotation. Source: Compara positive regulation of B cell differentiation Traceable author statement Ref.33. Source: UniProtKB positive regulation of NF-kappaB transcription factor activity Traceable author statement Ref.33. Source: UniProtKB regulation of B cell apoptotic process Traceable author statement Ref.33. Source: UniProtKB regulation of B cell cytokine production Traceable author statement Ref.33. Source: UniProtKB toll-like receptor 1 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 2 signaling pathway Traceable author statement. Source: Reactome toll-like receptor 4 signaling pathway Traceable author statement. Source: Reactome transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW
Cellular_component	cytoplasmic vesicle Inferred from electronic annotation. Source: Compara cytosol Inferred from direct assay PubMed 17823121. Source: UniProtKB membrane raft Inferred from direct assay PubMed 15046600. Source: HGNC nucleus Traceable author statement Ref.33. Source: UniProtKB plasma membrane Inferred from direct assay PubMed 17823121. Source: UniProtKB
Molecular_function	ATP binding Traceable author statement PubMed 11913944. Source: HGNC metal ion binding Inferred from electronic annotation. Source: UniProtKB-KW non-membrane spanning protein tyrosine kinase activity Traceable author statement Ref.33. Source: UniProtKB phosphatidylinositol-3,4,5-trisphosphate binding Inferred from direct assay PubMed 17823121. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		2	EBI-624835,EBI-624835
GTF2I	P78347	5	EBI-624835,EBI-359622
HSP90AB1	P08238	2	EBI-624835,EBI-352572
MAL	P21145	5	EBI-624835,EBI-3932027
PRKCQ	Q04759	2	EBI-624835,EBI-374762
SH3BP5	O60239	4	EBI-624835,EBI-624860

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Initiator methionine

1

1

Removed Ref.10

Chain

2 – 659

658

Tyrosine-protein kinase BTK

PRO_0000088065

Regions

Domain

3 – 133

131

PH

Domain

214 – 274

61

SH3

Domain

281 – 377

97

SH2

Domain

402 – 655

254

Protein kinase

Zinc finger

135 – 171

37

Btk-type

Nucleotide binding

408 – 416

9

ATP By similarity

Region

12 – 24

13

Inositol-(1,3,4,5)-tetrakisphosphate 1-binding

Region

474 – 479

6

Inhibitor-binding

Motif

581 – 588

8

CAV1-binding

Sites

Active site

521

1

Proton acceptor By similarity

Metal binding

143

1

Zinc

Metal binding

154

1

Zinc

Metal binding

155

1

Zinc

Metal binding

165

1

Zinc

Binding site

26

1

Inositol-(1,3,4,5)-tetrakisphosphate

Binding site

28

1

Inositol-(1,3,4,5)-tetrakisphosphate

Binding site

39

1

Inositol-(1,3,4,5)-tetrakisphosphate

Binding site

53

1

Inositol-(1,3,4,5)-tetrakisphosphate; via carbonyl oxygen

Binding site

430

1

ATP By similarity

Binding site

445

1

Inhibitor

Binding site

461

1

Inhibitor

Binding site

477

1

Inhibitor

Binding site

538

1

Inhibitor

Binding site

539

1

Inhibitor; via amide nitrogen

Binding site

542

1

Inhibitor; via carbonyl oxygen

Amino acid modifications

Modified residue

2

1

N-acetylalanine Ref.10

Modified residue

21

1

Phosphoserine Ref.26

Modified residue

40

1

Phosphotyrosine By similarity

Modified residue

55

1

Phosphoserine Ref.34

Modified residue

115

1

Phosphoserine Ref.26

Modified residue

180

1

Phosphoserine; by PKC/PRKCB Ref.21

Modified residue

191

1

Phosphothreonine Ref.34

Modified residue

223

1

Phosphotyrosine; by autocatalysis Ref.11 Ref.14 Ref.15 Ref.30

Modified residue

344

1

Phosphotyrosine By similarity

Modified residue

361

1

Phosphotyrosine Ref.34

Modified residue

551

1

Phosphotyrosine; by LYN and SYK Ref.14 Ref.15

Modified residue

617

1

Phosphotyrosine Ref.25

Modified residue

623

1

Phosphoserine Ref.25

Modified residue

659

1

Phosphoserine Ref.34

Natural variations

Natural variant

11

1

L → P in XLA.

VAR_006216

Natural variant

12

1

K → R in XLA. Ref.62

VAR_006217

Natural variant

14

1

S → F in XLA.

VAR_006218

Natural variant

19

1

K → E in XLA. Ref.67

VAR_008291

Natural variant

25

1

F → S in XLA. Ref.55

VAR_006219

Natural variant

27

1

K → R in XLA.

VAR_008292

Natural variant

28

1

R → C in XLA; no effect on phosphorylation of GTF2I.

VAR_008293

Natural variant

28

1

R → H in XLA; moderate. Ref.50 Ref.52 Ref.67

VAR_006220

Natural variant

28

1

R → P in XLA. Ref.62

VAR_006221

Natural variant

33

1

T → P in XLA; severe. Ref.52 Ref.57

VAR_006222

Natural variant

39

1

Y → S in XLA. Ref.70

VAR_008960

Natural variant

40

1

Y → C in XLA.

VAR_008294

Natural variant

40

1

Y → N in XLA.

VAR_008295

Natural variant

61

1

I → N in XLA. Ref.67

VAR_008296

Natural variant

64

1

V → D in XLA.

VAR_008297

Natural variant

64

1

V → F in XLA. Ref.54

VAR_006223

Natural variant

82

1

R → K. Ref.71
Corresponds to variant rs56035945 [ dbSNP | Ensembl ].

VAR_041676

Natural variant

103

1

Q → QSVFSSTR in XLA.

VAR_006224

Natural variant

113

1

V → D in XLA. Ref.51

VAR_006225

Natural variant

115

1

S → F in XLA.

VAR_008298

Natural variant

117

1

T → P in XLA. Ref.67

VAR_008299

Natural variant

127

1

Q → H in XLA. Ref.67

VAR_008300

Natural variant

154

1

C → S in XLA. Ref.64

VAR_008301

Natural variant

155

1

C → G in XLA.

VAR_008302

Natural variant

155

1

C → R in XLA. Ref.64 Ref.67

VAR_008303

Natural variant

184

1

T → P in XLA.

VAR_008304

Natural variant

190

1

P → K in a lung large cell carcinoma sample; somatic mutation; requires 2 nucleotide substitutions. Ref.71

VAR_041677

Natural variant

260 – 280

21

Missing in XLA; severe.

VAR_006226

Natural variant

288

1

R → Q in XLA. Ref.66

VAR_008305

Natural variant

288

1

R → W in XLA. Ref.49 Ref.50 Ref.55 Ref.63

VAR_006227

Natural variant

295

1

L → P in XLA. Ref.61 Ref.67

VAR_006228

Natural variant

302

1

G → E in XLA. Ref.59 Ref.62

VAR_006230

Natural variant

302

1

G → R in XLA.

VAR_008306

Natural variant

302

1

Missing in XLA. Ref.57

VAR_006229

Natural variant

307

1

R → G in XLA; loss of activity. Ref.49

VAR_006231

Natural variant

307

1

R → T in XLA. Ref.66

VAR_008307

Natural variant

308

1

D → E in XLA.

VAR_008308

Natural variant

319

1

V → A in XLA; moderate.

VAR_008309

Natural variant

334

1

Y → S in XLA. Ref.5

VAR_006232

Natural variant

358

1

L → F in XLA. Ref.60

VAR_006233

Natural variant

361

1

Y → C in XLA; mild. Ref.51
Corresponds to variant rs28935478 [ dbSNP | Ensembl ].

VAR_006234

Natural variant

362

1

H → Q in XLA.

VAR_006235

Natural variant

364

1

H → P in XLA.

VAR_006236

Natural variant

365

1

N → Y in XLA.

VAR_006237

Natural variant

366

1

S → F in XLA.

VAR_008310

Natural variant

369

1

L → F in XLA. Ref.67

VAR_008311

Natural variant

370

1

I → M in XLA. Ref.55

VAR_006238

Natural variant

372

1

R → G in XLA. Ref.67

VAR_008312

Natural variant

408

1

L → P in XLA; moderate. Ref.52

VAR_006239

Natural variant

414

1

G → R in XLA. Ref.67

VAR_008313

Natural variant

418

1

Y → H in XLA.

VAR_006240

Natural variant

429

1

I → N in XLA. Ref.58

VAR_006241

Natural variant

430

1

K → E in XLA; loss of phosphorylation of GTF2I. Ref.53

VAR_006242

Natural variant

430

1

K → R in XLA. Ref.66

VAR_008314

Natural variant

445

1

E → D in XLA. Ref.66

VAR_008315

Natural variant

462

1

G → D in XLA.

VAR_008316

Natural variant

462

1

G → V in XLA.

VAR_008317

Natural variant

476

1

Y → D in XLA. Ref.59

VAR_006243

Natural variant

477

1

M → R in XLA. Ref.58

VAR_006244

Natural variant

502

1

C → F in XLA.

VAR_006245

Natural variant

502

1

C → W in XLA. Ref.62

VAR_006246

Natural variant

506

1

C → R in XLA. Ref.5

VAR_006247

Natural variant

506

1

C → Y in XLA. Ref.67

VAR_006248

Natural variant

508

1

A → D in XLA.

VAR_008318

Natural variant

509

1

M → I in XLA.

VAR_008319

Natural variant

509

1

M → V in XLA. Ref.55

VAR_006249

Natural variant

512

1

L → P in XLA. Ref.70

VAR_008961

Natural variant

512

1

L → Q in XLA. Ref.70

VAR_008962

Natural variant

518

1

L → R in XLA.

VAR_008320

Natural variant

520

1

R → Q in XLA; severe; prevents activation due to absence of contact between the catalytic loop and the regulatory phosphorylated residue. Ref.5 Ref.51 Ref.53 Ref.57

VAR_006251

Natural variant

521

1

D → G in XLA. Ref.67

VAR_008321

Natural variant

521

1

D → H in XLA; severe. Ref.62

VAR_006252

Natural variant

521

1

D → N in XLA; severe.

VAR_006253

Natural variant

523

1

A → E in XLA.

VAR_008322

Natural variant

525

1

R → G in XLA. Ref.66

VAR_008323

Natural variant

525

1

R → P in XLA. Ref.55

VAR_006254

Natural variant

525

1

R → Q in XLA; severe; disturbs ATP-binding. Ref.53 Ref.67

VAR_006255

Natural variant

526

1

N → K in XLA. Ref.55

VAR_006256

Natural variant

535

1

V → F in XLA. Ref.66

VAR_008324

Natural variant

542

1

L → P in XLA; growth hormone deficiency. Ref.51

VAR_006257

Natural variant

544

1

R → G in XLA. Ref.70

VAR_008963

Natural variant

544

1

R → K in XLA. Ref.63

VAR_006258

Natural variant

559

1

F → S in XLA. Ref.67

VAR_008325

Natural variant

562

1

R → P in XLA. Ref.53 Ref.69
Corresponds to variant rs28935176 [ dbSNP | Ensembl ].

VAR_006259

Natural variant

562

1

R → W in XLA. Ref.5 Ref.51 Ref.55 Ref.67

VAR_006260

Natural variant

563

1

W → L in XLA. Ref.66

VAR_008326

Natural variant

567

1

E → K in XLA; severe. Ref.56

VAR_006261

Natural variant

578

1

S → Y in XLA. Ref.70

VAR_008964

Natural variant

581

1

W → R in XLA.

VAR_006262

Natural variant

582

1

A → V in XLA. Ref.53 Ref.55

VAR_006263

Natural variant

583

1

F → S in XLA.

VAR_008327

Natural variant

587

1

M → L in XLA; mild. Ref.56

VAR_006264

Natural variant

589

1

E → D in XLA.

VAR_008328

Natural variant

589

1

E → G in XLA; moderate; interferes with substrate binding. Ref.52 Ref.53

VAR_006265

Natural variant

589

1

E → K in XLA. Ref.70

VAR_008965

Natural variant

592

1

S → P in XLA. Ref.63

VAR_006267

Natural variant

594

1

G → E in XLA; mild; interferes with substrate binding. Ref.53 Ref.67

VAR_006268

Natural variant

594

1

G → R in XLA. Ref.55

VAR_006269

Natural variant

598

1

Y → C in XLA.

VAR_006270

Natural variant

607

1

A → D in XLA; mild. Ref.49

VAR_006271

Natural variant

613

1

G → D in XLA; mild; interferes with substrate binding and/or domain interactions. Ref.52 Ref.53

VAR_006272

Natural variant

619

1

P → A in XLA.

VAR_008330

Natural variant

619

1

P → S in XLA.

VAR_006273

Natural variant

619

1

P → T in XLA. Ref.67

VAR_008331

Natural variant

622

1

A → P in XLA. Ref.66

VAR_008332

Natural variant

626

1

V → G in XLA. Ref.67

VAR_008333

Natural variant

630

1

M → I Polymorphism, 35%.

VAR_006274

Natural variant

630

1

M → K in XLA. Ref.5 Ref.51

VAR_006275

Natural variant

630

1

M → T in XLA.

VAR_008334

Natural variant

633

1

C → Y in XLA. Ref.62

VAR_006276

Natural variant

641

1

R → C in XLA. Ref.57

VAR_006277

Natural variant

641

1

R → H in XLA; severe. Ref.56 Ref.67

VAR_006278

Natural variant

644

1

F → L in XLA.

VAR_008335

Natural variant

644

1

F → S in XLA. Ref.62

VAR_006279

Natural variant

647

1

L → P in XLA.

VAR_006280

Natural variant

652

1

L → P in XLA. Ref.51

VAR_006281

Experimental info

Mutagenesis

41

1

E → K: No effect on phosphorylation of GTF2I. Ref.15 Ref.16

Mutagenesis

189

1

P → A: No effect on phosphorylation of GTF2I. Ref.15 Ref.16

Mutagenesis

223

1

Y → F: Loss of phosphorylation of GTF2I. Ref.14 Ref.15 Ref.16

Mutagenesis

251 – 252

2

WW → LL: Large decrease in binding by SH3BP5. Ref.15 Ref.16

Mutagenesis

251

1

W → L: No effect on phosphorylation of GTF2I. Ref.15 Ref.16

Mutagenesis

307

1

R → K: Loss of phosphorylation of GTF2I. Ref.15 Ref.16

Mutagenesis

551

1

Y → F: Loss of phosphorylation of GTF2I. Ref.15 Ref.16

Mutagenesis

617

1

Y → E: Defective in mediating calcium response. Ref.16 Ref.25

Secondary structure

1

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659

Helix Strand Turn

Details...

Beta strand

6 – 13

8

Beta strand

18 – 20

3

Beta strand

25 – 32

8

Beta strand

34 – 43

10

Turn

44 – 47

4

Beta strand

48 – 57

10

Helix

58 – 60

3

Beta strand

61 – 66

6

Helix

75 – 77

3

Helix

93 – 96

4

Beta strand

100 – 106

7

Beta strand

111 – 116

6

Helix

118 – 132

15

Beta strand

140 – 142

3

Beta strand

149 – 152

4

Turn

153 – 155

3

Beta strand

165 – 167

3

Turn

212 – 215

4

Beta strand

218 – 223

6

Beta strand

228 – 232

5

Beta strand

240 – 242

3

Beta strand

248 – 252

5

Turn

257 – 259

3

Beta strand

261 – 265

5

Turn

266 – 268

3

Beta strand

279 – 282

4

Helix

288 – 298

11

Beta strand

303 – 308

6

Beta strand

310 – 312

3

Beta strand

315 – 326

12

Beta strand

330 – 335

6

Beta strand

337 – 339

3

Turn

340 – 342

3

Beta strand

343 – 347

5

Beta strand

350 – 354

5

Helix

355 – 363

9

Beta strand

373 – 376

4

Helix

393 – 395

3

Helix

399 – 401

3

Beta strand

402 – 409

8

Turn

411 – 413

3

Beta strand

414 – 421

8

Turn

422 – 424

3

Beta strand

425 – 432

8

Helix

439 – 450

12

Beta strand

460 – 464

5

Beta strand

466 – 474

9

Helix

482 – 487

6

Helix

489 – 491

3

Helix

495 – 514

20

Helix

524 – 526

3

Beta strand

527 – 529

3

Beta strand

535 – 537

3

Helix

542 – 545

4

Helix

549 – 552

4

Turn

554 – 556

3

Helix

561 – 563

3

Helix

566 – 571

6

Helix

576 – 591

16

Turn

592 – 594

3

Turn

597 – 600

4

Helix

603 – 611

9

Helix

624 – 632

9

Helix

638 – 640

3

Helix

644 – 657

14

Sequences

	Sequence		Length	Mass (Da)
	Q06187 [UniParc]. Last modified January 23, 2007. Version 3. Checksum: DF06B5D1FEC257CC	FASTA	659	76,281
	10 20 30 40 50 60 MAAVILESIF LKRSQQKKKT SPLNFKKRLF LLTVHKLSYY EYDFERGRRG SKKGSIDVEK 70 80 90 100 110 120 ITCVETVVPE KNPPPERQIP RRGEESSEME QISIIERFPY PFQVVYDEGP LYVFSPTEEL 130 140 150 160 170 180 RKRWIHQLKN VIRYNSDLVQ KYHPCFWIDG QYLCCSQTAK NAMGCQILEN RNGSLKPGSS 190 200 210 220 230 240 HRKTKKPLPP TPEEDQILKK PLPPEPAAAP VSTSELKKVV ALYDYMPMNA NDLQLRKGDE 250 260 270 280 290 300 YFILEESNLP WWRARDKNGQ EGYIPSNYVT EAEDSIEMYE WYSKHMTRSQ AEQLLKQEGK 310 320 330 340 350 360 EGGFIVRDSS KAGKYTVSVF AKSTGDPQGV IRHYVVCSTP QSQYYLAEKH LFSTIPELIN 370 380 390 400 410 420 YHQHNSAGLI SRLKYPVSQQ NKNAPSTAGL GYGSWEIDPK DLTFLKELGT GQFGVVKYGK 430 440 450 460 470 480 WRGQYDVAIK MIKEGSMSED EFIEEAKVMM NLSHEKLVQL YGVCTKQRPI FIITEYMANG 490 500 510 520 530 540 CLLNYLREMR HRFQTQQLLE MCKDVCEAME YLESKQFLHR DLAARNCLVN DQGVVKVSDF 550 560 570 580 590 600 GLSRYVLDDE YTSSVGSKFP VRWSPPEVLM YSKFSSKSDI WAFGVLMWEI YSLGKMPYER 610 620 630 640 650 FTNSETAEHI AQGLRLYRPH LASEKVYTIM YSCWHEKADE RPTFKILLSN ILDVMDEES

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases." Vetrie D., Vorechovsky I., Sideras P., Holland J., Davies A., Flinter F., Hammarstroem L., Kinnon C., Levinsky R.J., Bobrow M., Smith C.I.E., Bentley D.R. Nature 361:226-233(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	Erratum Vetrie D., Vorechovsky I., Sideras P., Holland J., Davies A., Flinter F., Hammarstroem L., Kinnon C., Levinsky R.J., Bobrow M., Smith C.I.E., Bentley D.R. Nature 364:362-362(1993)
[3]	"Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia." Ohta Y., Haire R.N., Litman R.T., Fu S.M., Nelson R.P., Kratz J., Kornfeld S.J., la Morena M., Good R.A., Litman G.W. Proc. Natl. Acad. Sci. U.S.A. 91:9062-9066(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]. Tissue: Blood.
[4]	"The genomic structure of human BTK, the defective gene in X-linked agammaglobulinemia." Rohrer J., Parolini O., Belmont J.W., Conley M.E. Immunogenetics 40:319-324(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]	"Genomic organization of the Btk gene and exon scanning for mutations in patients with X-linked agammaglobulinemia." Hagemann T.L., Chen Y., Rosen F.S., Kwan S.-P. Hum. Mol. Genet. 3:1743-1749(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS XLA SER-334; ARG-506; GLN-520; TRP-562 AND LYS-630.
[6]	"Sixty-nine kilobases of contiguous human genomic sequence containing the alpha-galactosidase A and Bruton's tyrosine kinase loci." Oeltjen J.C., Liu X., Lu J., Allen R.C., Muzny D.M., Belmont J.W., Gibbs R.A. Mamm. Genome 6:334-338(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[7]	"The DNA sequence of the human X chromosome." Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R. Nature 434:325-337(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[9]	"Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia." Tsukada S., Saffran D.C., Rawlings D.J., Parolini O., Allen R.C., Klisak I., Sparkes R.S., Kubagawa H., Mohandas T., Quan S., Belmont J.W., Cooper M.D., Conley M.E., Witte O.N. Cell 72:279-290(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE OF 1-442.
[10]	Bienvenut W.V., Claeys D. Submitted (NOV-2005) to UniProtKB Cited for: PROTEIN SEQUENCE OF 2-12 AND 323-332, CLEAVAGE OF INITIATOR METHIONINE, ACETYLATION AT ALA-2, MASS SPECTROMETRY. Tissue: Platelet.
[11]	"Identification of phosphorylation sites within the SH3 domains of Tec family tyrosine kinases." Nore B.F., Mattsson P.T., Antonsson P., Backesjo C.-M., Westlund A., Lennartsson J., Hansson H., Low P., Ronnstrand L., Smith C.I.E. Biochim. Biophys. Acta 1645:123-132(2003) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 219-235, PHOSPHORYLATION AT TYR-223.
[12]	"An exon-skipping mutation in the btk gene of a patient with X-linked agammaglobulinemia and isolated growth hormone deficiency." Duriez B., Duquesnoy P., Dastot F., Bougneres P., Amselem S., Goossens M. FEBS Lett. 346:165-170(1994) [PubMed] [Europe PMC] [Abstract] Cited for: INVOLVEMENT IN XLA-IGHD.
[13]	"Tec homology (TH) adjacent to the PH domain." Vihinen M., Nilsson L., Smith C.I. FEBS Lett. 350:263-265(1994) [PubMed] [Europe PMC] [Abstract] Cited for: DOMAIN PH.
[14]	"Regulation of Btk function by a major autophosphorylation site within the SH3 domain." Park H., Wahl M.I., Afar D.E., Turck C.W., Rawlings D.J., Tam C., Scharenberg A.M., Kinet J.P., Witte O.N. Immunity 4:515-525(1996) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT TYR-223 AND TYR-551, MUTAGENESIS OF TYR-223, ENZYME REGULATION.
[15]	"BAP-135, a target for Bruton's tyrosine kinase in response to B cell receptor engagement." Yang W., Desiderio S. Proc. Natl. Acad. Sci. U.S.A. 94:604-609(1997) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF GTF2I, PHOSPHORYLATION AT TYR-223 AND TYR-551, MUTAGENESIS OF GLU-41; PRO-189; TYR-223; TRP-251; ARG-307 AND TYR-551.
[16]	"Identification and characterization of a novel SH3-domain binding protein, Sab, which preferentially associates with Bruton's tyrosine kinase (Btk)." Matsushita M., Yamadori T., Kato S., Takemoto Y., Inazawa J., Baba Y., Hashimoto S., Sekine S., Arai S., Kunikata T., Kurimoto M., Kishimoto T., Tsukada S. Biochem. Biophys. Res. Commun. 245:337-343(1998) [PubMed] [Europe PMC] [Abstract] Cited for: MUTAGENESIS OF 251-TRP-TRP-252, INTERACTION WITH SH3BP5.
[17]	"Phosphatidylinositol 3-kinase-dependent membrane association of the Bruton's tyrosine kinase pleckstrin homology domain visualized in single living cells." Varnai P., Rother K.I., Balla T. J. Biol. Chem. 274:10983-10989(1999) [PubMed] [Europe PMC] [Abstract] Cited for: DOMAIN PH, SUBCELLULAR LOCATION.
[18]	"Bruton's tyrosine kinase activity is negatively regulated by Sab, the Btk-SH3 domain-binding protein." Yamadori T., Baba Y., Mastushita M., Hashimoto S., Kurosaki M., Kurosaki T., Kishimoto T., Tsukada S. Proc. Natl. Acad. Sci. U.S.A. 96:6341-6346(1999) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SH3BP5, ENZYME REGULATION.
[19]	"Redistribution of Bruton's tyrosine kinase by activation of phosphatidylinositol 3-kinase and Rho-family GTPases." Nore B.F., Vargas L., Mohamed A.J., Branden L.J., Backesjo C.M., Islam T.C., Mattsson P.T., Hultenby K., Christensson B., Smith C.I. Eur. J. Immunol. 30:145-154(2000) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[20]	"Nucleocytoplasmic shuttling of Bruton's tyrosine kinase." Mohamed A.J., Vargas L., Nore B.F., Backesjo C.M., Christensson B., Smith C.I. J. Biol. Chem. 275:40614-40619(2000) [PubMed] [Europe PMC] [Abstract] Cited for: SUBCELLULAR LOCATION.
[21]	"PKCbeta modulates antigen receptor signaling via regulation of Btk membrane localization." Kang S.W., Wahl M.I., Chu J., Kitaura J., Kawakami Y., Kato R.M., Tabuchi R., Tarakhovsky A., Kawakami T., Turck C.W., Witte O.N., Rawlings D.J. EMBO J. 20:5692-5702(2001) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT SER-180, ENZYME REGULATION.
[22]	"Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme function in B-cell signaling." Rodriguez R., Matsuda M., Perisic O., Bravo J., Paul A., Jones N.P., Light Y., Swann K., Williams R.L., Katan M. J. Biol. Chem. 276:47982-47992(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF PLCG2.
[23]	"Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding protein." Liu W., Quinto I., Chen X., Palmieri C., Rabin R.L., Schwartz O.M., Nelson D.L., Scala G. Nat. Immunol. 2:939-946(2001) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH IBTK, ENZYME REGULATION.
[24]	"Functional interaction of caveolin-1 with Bruton's tyrosine kinase and Bmx." Vargas L., Nore B.F., Berglof A., Heinonen J.E., Mattsson P.T., Smith C.I., Mohamed A.J. J. Biol. Chem. 277:9351-9357(2002) [PubMed] [Europe PMC] [Abstract] Cited for: DOMAIN, PH INTERACTION WITH CAV1, SUBCELLULAR LOCATION, ENZYME REGULATION.
[25]	"A phosphorylation site in Bruton's tyrosine kinase selectively regulates B cell calcium signaling efficiency by altering phospholipase C-gamma activation." Guo S., Ferl G.Z., Deora R., Riedinger M., Yin S., Kerwin J.L., Loo J.A., Witte O.N. Proc. Natl. Acad. Sci. U.S.A. 101:14180-14185(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION AT TYR-617 AND SER-623, MUTAGENESIS OF TYR-617.
[26]	"Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase Pin1." Yu L., Mohamed A.J., Vargas L., Berglof A., Finn G., Lu K.P., Smith C.I. J. Biol. Chem. 281:18201-18207(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH PIN1, PHOSPHORYLATION AT SER-21 AND SER-115, ENZYME REGULATION.
[27]	"Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF, but not IL-6, production." Horwood N.J., Page T.H., McDaid J.P., Palmer C.D., Campbell J., Mahon T., Brennan F.M., Webster D., Foxwell B.M. J. Immunol. 176:3635-3641(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN THE TLR PATHWAY.
[28]	"Induction of immunoglobulin heavy-chain transcription through the transcription factor Bright requires TFII-I." Rajaiya J., Nixon J.C., Ayers N., Desgranges Z.P., Roy A.L., Webb C.F. Mol. Cell. Biol. 26:4758-4768(2006) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH GTF2I AND ARID3A, FUNCTION.
[29]	"Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation." Mansell A., Smith R., Doyle S.L., Gray P., Fenner J.E., Crack P.J., Nicholson S.E., Hilton D.J., O'Neill L.A., Hertzog P.J. Nat. Immunol. 7:148-155(2006) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF TIRAP, ENZYME REGULATION.
[30]	"Signaling by Toll-like receptors 8 and 9 requires Bruton's tyrosine kinase." Doyle S.L., Jefferies C.A., Feighery C., O'Neill L.A. J. Biol. Chem. 282:36953-36960(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, INTERACTION WITH TLR8 AND TLR9, ENZYME REGULATION, PHOSPHORYLATION AT TYR-223.
[31]	"Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening." Voss M., Lettau M., Janssen O. BMC Immunol. 10:53-53(2009) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH FASLG.
[32]	"Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis." Uckun F.M. Biochem. Pharmacol. 56:683-691(1998) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION IN REGULATION OF APOPTOSIS.
[33]	"Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain." Mohamed A.J., Yu L., Backesjo C.M., Vargas L., Faryal R., Aints A., Christensson B., Berglof A., Vihinen M., Nore B.F., Smith C.I. Immunol. Rev. 228:58-73(2009) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON FUNCTION, REVIEW ON ENZYME REGULATION.
[34]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-55; THR-191; TYR-361 AND SER-659, MASS SPECTROMETRY.
[35]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[36]	"Structure of the PH domain and Btk motif from Bruton's tyrosine kinase: molecular explanations for X-linked agammaglobulinaemia." Hyvoenen M., Saraste M. EMBO J. 16:3396-3404(1997) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 2-170 IN COMPLEX WITH ZINC.
[37]	"Solution structure of the SH3 domain from Bruton's tyrosine kinase." Hansson H., Mattsson P.T., Allard P., Haapaniemi P., Vihinen M., Smith C.I.E., Haerd T. Biochemistry 37:2912-2924(1998) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 212-275.
[38]	"Structure of the PH domain from Bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate." Baraldi E., Carugo K.D., Hyvoenen M., Surdo P.L., Riley A.M., Potter B.V.L., O'Brien R., Ladbury J.E., Saraste M. Structure 7:449-460(1999) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1-170 IN COMPLEX WITH INOSITOL-(1,3,4,5)-TETRAKISPHOSPHATE AND ZINC, DOMAIN PH.
[39]	"Solution structure of the human BTK SH3 domain complexed with a proline-rich peptide from p120cbl." Tzeng S.R., Lou Y.C., Pai M.T., Jain M.L., Cheng J.W. J. Biomol. NMR 16:303-312(2000) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 216-273.
[40]	"Crystal structure of Bruton's tyrosine kinase domain suggests a novel pathway for activation and provides insights into the molecular basis of X-linked agammaglobulinemia." Mao C., Zhou M., Uckun F.M. J. Biol. Chem. 276:41435-41443(2001) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 397-659.
[41]	"Solution structure and phosphopeptide binding of the SH2 domain from the human Bruton's tyrosine kinase." Huang K.C., Cheng H.T., Pai M.T., Tzeng S.R., Cheng J.W. J. Biomol. NMR 36:73-78(2006) [PubMed] [Europe PMC] [Abstract] Cited for: STRUCTURE BY NMR OF 270-386.
[42]	"A novel, specific Btk inhibitor antagonizes BCR and Fc[gamma]R signaling and suppresses inflammatory arthritis." Di Paolo J.A., Huang T., Balazs M., Barbosa J., Barck K.H., Carano R.A.D., Darrow J., Davies D.R., DeForge L.E., Dennis G. Jr., Diehl L., Ferrando R. Submitted (AUG-2010) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 393-656 IN COMPLEX WITH INHIBITOR.
[43]	"Crystal structure of PH domain of Bruton's tyrosine kinase." Murayama K., Kato-Murayama M., Mishima C., Shirouzu M., Yokoyama S. Submitted (MAY-2007) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.58 ANGSTROMS) OF 2-170 IN COMPLEX WITH INHIBITOR AND ZINC.
[44]	"Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases." Marcotte D.J., Liu Y.T., Arduini R.M., Hession C.A., Miatkowski K., Wildes C.P., Cullen P.F., Hong V., Hopkins B.T., Mertsching E., Jenkins T.J., Romanowski M.J., Baker D.P., Silvian L.F. Protein Sci. 19:429-439(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 382-659 IN COMPLEX WITH INHIBITOR DASATINIB.
[45]	"A novel, specific BTK inhibitor antagonizes BCR and FcgR signaling and suppresses inflammatory arthritis." Di Paolo J., Huang T., Balazs M., Barbosa J., Barck K.H., Bravo B., Carano R.A.D., Darrow J., Davies D.R., DeForge L.E., Diehl L., Ferrando R., Gallion S.L., Gianetti A.M., Gribling P., Hurez V., Hymowitz S.G., Jones R. , Kropf J.E., Lee W.P., Maciejewski P.M., Mitchell S.A., Rong H., Staker B.L., Whitney J.A., Yeh S., Young W., Yu C., Zhang J., Reif K., Currie K.S. Submitted (SEP-2010) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 393-659.
[46]	"Insights into the conformational flexibility of Bruton's tyrosine kinase from multiple ligand complex structures." Kuglstatter A., Wong A., Tsing S., Lee S.W., Lou Y., Villasenor A.G., Bradshaw J.M., Shaw D., Barnett J.W., Browner M.F. Protein Sci. 20:428-436(2011) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 387-659 IN COMPLEX WITH INHIBITOR.
[47]	"BTKbase, mutation database for X-linked agammaglobulinemia (XLA)." Vihinen M., Iwata T., Kinnon C., Kwan S.-P., Ochs H.D., Vorechovsky I., Smith C.I.E. Nucleic Acids Res. 24:160-165(1996) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON VARIANTS XLA.
[48]	"BTKbase, mutation database for X-linked agammaglobulinemia (XLA)." Vihinen M., Belohradsky B.H., Haire R.N., Holinski-Feder E., Kwan S.-P., Lappalainen I., Lehvaeslaiho H., Lester T., Meindl A., Ochs H.D., Ollila J., Vorechovsky I., Weiss M., Smith C.I.E. Nucleic Acids Res. 25:166-171(1997) [PubMed] [Europe PMC] [Abstract] Cited for: REVIEW ON VARIANTS XLA.
[49]	"Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis." Bradley L.A.D., Sweatman A.K., Lovering R.C., Jones A.M., Morgan G., Levinsky R.J., Kinnon C. Hum. Mol. Genet. 3:79-83(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA TRP-288; GLY-307; ASP-607 AND SER-VAL-PHE-SER-SER-THR-ARG-103 INS.
[50]	"Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice." de Weers M., Mensink R.G.J., Kraakman M.E.M., Schuurman R.K.B., Hendriks R.W. Hum. Mol. Genet. 3:161-166(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA HIS-28 AND TRP-288.
[51]	"Screening of genomic DNA to identify mutations in the gene for Bruton's tyrosine kinase." Conley M.E., Fitch-Hilgenberg M.E., Cleveland J.L., Parolini O., Rohrer J. Hum. Mol. Genet. 3:1751-1756(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA ASP-113; CYS-361; GLN-520; PRO-542; TRP-562; LYS-630 AND PRO-652.
[52]	"Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families." Zhu Q., Zhang M., Winkelstein J., Chen S.-H., Ochs H.D. Hum. Mol. Genet. 3:1899-1900(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA HIS-28; PRO-33; PRO-408; GLY-589; ASP-613 AND 260-GLN--GLU-280 DEL.
[53]	"Structural basis for chromosome X-linked agammaglobulinemia: a tyrosine kinase disease." Vihinen M., Vetrie D., Maniar H.S., Ochs H.D., Zhu Q., Vorechovsky I., Webster A.D.B., Notarangelo L.D., Nilsson L., Sowadski J.M., Smith C.I.E. Proc. Natl. Acad. Sci. U.S.A. 91:12803-12807(1994) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA GLU-430; GLN-520; GLN-525; PRO-562; VAL-582; GLY-589; GLU-594 AND ASP-613.
[54]	"Structural basis for pleckstrin homology domain mutations in X-linked agammaglobulinemia." Vihinen M., Zvelebil J.J.M., Zhu Q., Brooimans R.A., Ochs H.D., Zegers B.J.M., Nilsson L., Waterfield M.D., Smith C.I.E. Biochemistry 34:1475-1481(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT XLA PHE-64, CHARACTERIZATION OF OTHER XLA VARIANTS.
[55]	"DNA-based mutation analysis of Bruton's tyrosine kinase gene in patients with X-linked agammaglobulinaemia." Vorechovsky I., Vihinen M., de Saint Basile G., Honsova S., Hammarstroem L., Mueller S., Nilsson L., Fischer A., Smith C.I.E. Hum. Mol. Genet. 4:51-58(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA SER-25; TRP-288; MET-370; VAL-509; PRO-525; LYS-526; TRP-562; VAL-582 AND ARG-594.
[56]	"Identification of Btk mutations in 20 unrelated patients with X-linked agammaglobulinaemia (XLA)." Jin H., Webster A.D.B., Vihinen M., Sideras P., Vorechovsky I., Hammarstroem L., Bernatowska-Matuszkiewicz E., Smith C.I.E., Bobrow M., Vetrie D. Hum. Mol. Genet. 4:693-700(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA LYS-567; LEU-587 AND HIS-641.
[57]	"Mutation analysis in Bruton's tyrosine kinase, the X-linked agammaglobulinaemia gene, including identification of an insertional hotspot." Gaspar H.B., Bradley L.A.D., Katz F., Lovering R.C., Roifman C.M., Morgan G., Levinsky R.J., Kinnon C. Hum. Mol. Genet. 4:755-757(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA PRO-33; GLY-302 DEL; GLN-520 AND CYS-641.
[58]	"Improved oligonucleotide primer set for molecular diagnosis of X-linked agammaglobulinaemia: predominance of amino acid substitutions in the catalytic domain of Bruton's tyrosine kinase." Vorechovsky I., Luo L., de Saint Basile G., Hammarstroem L., Webster A.D.B., Smith C.I.E. Hum. Mol. Genet. 4:2403-2405(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA ASN-429 AND ARG-477.
[59]	"Characterization of germline mutations of the gene encoding Bruton's tyrosine kinase in families with X-linked agammaglobulinemia." Hagemann T.L., Rosen F.S., Kwan S.-P. Hum. Mutat. 5:296-302(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA GLU-302 AND ASP-476.
[60]	"A new point mutation involving a highly conserved leucine in the Btk SH2 domain in a family with X linked agammaglobulinaemia." Ohashi Y., Tsuchiya S., Konno T. J. Med. Genet. 32:77-79(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT XLA PHE-358.
[61]	"Detection of a novel mutation in the SRC homology domain 2 (SH2) of Bruton's tyrosine kinase and direct female carrier evaluation in a family with X-linked agammaglobulinemia." Schuster V., Seidenspinner S., Kreth H.W. Am. J. Med. Genet. 63:318-322(1996) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT XLA PRO-295.
[62]	"Identification of Bruton's tyrosine kinase (Btk) gene mutations and characterization of the derived proteins in 35 X-linked agammaglobulinemia families: a nationwide study of Btk deficiency in Japan." Hashimoto S., Tsukada S., Matsushita M., Miyawaki T., Niida Y., Yachie A., Kobayashi S., Iwata T., Hayakawa H., Matsuoka H., Tsuge I., Yamadori T., Kunikata T., Arai S., Yoshizaki K., Taniguchi N., Kishimoto T. Blood 88:561-573(1996) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA ARG-12; PRO-28; GLU-302; TRP-502; HIS-521; TYR-633 AND SER-644.
[63]	"Mutations of the Btk gene in 12 unrelated families with X-linked agammaglobulinemia in Japan." Kobayashi S., Iwata T., Saito M., Iwasaki R., Matsumoto H., Naritaka S., Kono Y., Hayashi Y. Hum. Genet. 97:424-430(1996) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA TRP-288; LYS-544 AND PRO-592.
[64]	"Missense mutations affecting a conserved cysteine pair in the TH domain of Btk." Vihinen M., Nore B., Mattsson P.T., Backesj C.-M., Nars M., Koutaniemi S., Watanabe C., Lester T., Jones A.M., Ochs H.D., Smith C.I.E. FEBS Lett. 413:205-210(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA SER-154 AND ARG-155.
[65]	"Molecular and structural characterization of five novel mutations in the Bruton's tyrosine kinase gene from patients with X-linked agammaglobulinemia." Saha B.K., Curtis S.K., Vogler L.B., Vihinen M. Mol. Med. 3:477-485(1997) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA.
[66]	"Mutations in btk in patients with presumed X-linked agammaglobulinemia." Conley M.E., Mathias D., Treadaway J., Minegishi Y., Rohrer J. Am. J. Hum. Genet. 62:1034-1043(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA GLN-288; THR-307; ARG-430; ASP-445; GLY-525; PHE-535; LEU-563 AND PRO-622.
[67]	"Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course." Holinski-Feder E., Weiss M., Brandau O., Jedele K.B., Nore B., Baeckesjoe C.-M., Vihinen M., Hubbard S.R., Belohradsky B.H., Smith C.I.E., Meindl A. Pediatrics 101:276-284(1998) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA GLU-19; HIS-28; ASN-61; PRO-117; HIS-127; ARG-155; PRO-295; PHE-369; GLY-372; ARG-414; TYR-506; GLY-521; GLN-525; SER-559; TRP-562; GLU-594; THR-619; GLY-626 AND HIS-641.
[68]	"Mutations of the human BTK gene coding for Bruton tyrosine kinase in X-linked agammaglobulinemia." Vihinen M., Kwan S.-P., Lester T., Ochs H.D., Resnick I., Vaeliaho J., Conley M.E., Smith C.I.E. Hum. Mutat. 13:280-285(1999) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA.
[69]	"Twin carriers of X-linked agammaglobulinemia (XLA) due to germline mutation in the Btk gene." Curtis S.K., Hebert M.D., Saha B.K. Am. J. Med. Genet. 90:229-232(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT XLA PRO-562.
[70]	"Identification of nine novel mutations in the Bruton's tyrosine kinase gene in X-linked agammaglobulinaemia patients." Orlandi P., Ritis K., Moschese V., Angelini F., Arvanitidis K., Speletas M., Sideras P., Plebani A., Rossi P. Hum. Mutat. 15:117-117(2000) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS XLA SER-39; PRO-512; GLN-512; GLY-544; TYR-578 AND LYS-589.
[71]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] LYS-82 AND LYS-190.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

BTKbase

BTK mutation db

GeneReviews

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X58957 mRNA. Translation: CAA41728.1.
U10087 , U10084, U10085, U10086 Genomic DNA. Translation: AAB60639.1.
L31572 , L31557, L31558, L31559, L31561, L31563, L31564, L31565, L31566, L31567, L31568, L31569, L31570, L31571 Genomic DNA. Translation: AAA61479.1.
U13433 , U13410, U13412, U13413, U13414, U13415, U13416, U13417, U13422, U13423, U13424, U13425, U13427, U13428, U13429, U13430, U13431, U13432 Genomic DNA. Translation: AAC51347.1.
U78027 Genomic DNA. Translation: AAB64205.1.
AL035422 Genomic DNA. Translation: CAB55876.1.
BC109079 mRNA. Translation: AAI09080.1.
BC109080 mRNA. Translation: AAI09081.1.

IPI

IPI00029132.

PIR

A45184. I37212.

RefSeq

NP_000052.1. NM_000061.2.

UniGene

Hs.159494.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1AWW	NMR	-	A	212-275	[»]
1AWX	NMR	-	A	212-275	[»]
1B55	X-ray	2.40	A/B	2-170	[»]
1BTK	X-ray	1.60	A/B	2-170	[»]
1BWN	X-ray	2.10	A/B	2-170	[»]
1K2P	X-ray	2.10	A/B	397-659	[»]
1QLY	NMR	-	A	216-273	[»]
2GE9	NMR	-	A	270-386	[»]
2Z0P	X-ray	2.58	A/B/C/D	2-170	[»]
3GEN	X-ray	1.60	A	382-659	[»]
3K54	X-ray	1.94	A	382-659	[»]
3OCS	X-ray	1.80	A	393-657	[»]
3OCT	X-ray	1.95	A	393-656	[»]
3P08	X-ray	2.30	A/B	393-659	[»]
3PIX	X-ray	1.85	A	387-659	[»]
3PIY	X-ray	2.55	A	387-659	[»]
3PIZ	X-ray	2.21	A	387-659	[»]
3PJ1	X-ray	2.00	A	387-659	[»]
3PJ2	X-ray	1.75	A	387-659	[»]
3PJ3	X-ray	1.85	A	387-659	[»]

ProteinModelPortal

Q06187.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-34071N.

IntAct

Q06187. 34 interactions.

MINT

MINT-110243.

STRING

9606.ENSP00000308176.

PTM databases

PhosphoSite

Q06187.

Polymorphism databases

DMDM

547759.

Proteomic databases

PaxDb

Q06187.

PRIDE

Q06187.

Protocols and materials databases

DNASU

695.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000308731; ENSP00000308176; ENSG00000010671.
ENST00000593575; ENSP00000469726; ENSG00000268897.

GeneID

695.

KEGG

hsa:695.

UCSC

uc004ehg.2. human.

Organism-specific databases

CTD

695.

GeneCards

GC0XM100604.

HGNC

HGNC:1133. BTK.

HPA

CAB016689.
HPA001198.
HPA002028.

MIM

300300. gene.
300755. phenotype.
307200. phenotype.

neXtProt

NX_Q06187.

Orphanet

47. X-linked agammaglobulinemia.

PharmGKB

PA25454.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233859.

HOVERGEN

HBG008761.

InParanoid

Q06187.

KO

K07370.

OMA

HEKAEER.

OrthoDB

EOG4DR9BX.

PhylomeDB

Q06187.

Enzyme and pathway databases

BRENDA

2.7.10.2. 2681.

Pathway_Interaction_DB

bcr_5pathway. BCR signaling pathway.
pi3kcipathway. Class I PI3K signaling events.
epopathway. EPO signaling pathway.
fcer1pathway. Fc-epsilon receptor I signaling in mast cells.

Reactome

REACT_6900. Immune System.

Gene expression databases

ArrayExpress

Q06187.

Bgee

Q06187.

CleanEx

HS_BTK.

Genevestigator

Q06187.

GermOnline

ENSG00000010671. Homo sapiens.

Family and domain databases

Gene3D

2.30.29.30. 1 hit.
3.30.505.10. 1 hit.

InterPro

IPR011009. Kinase-like_dom.
IPR011993. PH_like_dom.
IPR001849. Pleckstrin_homology.
IPR000719. Prot_kinase_cat_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]

Pfam

PF00779. BTK. 1 hit.
PF00169. PH. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF00017. SH2. 1 hit.
PF00018. SH3_1. 1 hit.
[Graphical view]

PRINTS

PR00401. SH2DOMAIN.
PR00452. SH3DOMAIN.
PR00402. TECBTKDOMAIN.
PR00109. TYRKINASE.

SMART

SM00107. BTK. 1 hit.
SM00233. PH. 1 hit.
SM00252. SH2. 1 hit.
SM00326. SH3. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]

SUPFAM

SSF56112. Kinase_like. 1 hit.
SSF50044. SH3. 1 hit.

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.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

Q06187.

ChEMBL

CHEMBL5251.

EvolutionaryTrace

Q06187.

GenomeRNAi

695.

NextBio

2850.

SOURCE

Search...

Entry information

Entry name

BTK_HUMAN

Accession

Primary (citable) accession number: Q06187
Secondary accession number(s): Q32ML5

Entry history

Integrated into UniProtKB/Swiss-Prot:	June 1, 1994
Last sequence update:	January 23, 2007
Last modified:	May 1, 2013
This is version 172 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.