CPLM 1.0 - Compendium of Protein Lysine Modification
TagContent
CPLM ID CPLM-011371
UniProt Accession
Genbank Protein ID
Genbank Nucleotide ID
Protein Name
 Tyrosine-protein kinase BTK 
Protein Synonyms/Alias
 Agammaglobulinemia tyrosine kinase; ATK; B-cell progenitor kinase; BPK; Bruton tyrosine kinase 
Gene Name
 BTK 
Gene Synonyms/Alias
 AGMX1; ATK; BPK 
Created Date
 July 27, 2013 
Organism
 Homo sapiens (Human) 
NCBI Taxa ID
 9606 
Lysine Modification
Position
Peptide
Type
References
322YTVSVFAKSTGDPQGubiquitination[1, 2]
406PKDLTFLKELGTGQFubiquitination[1, 2, 3]
536VNDQGVVKVSDFGLSubiquitination[3]
Reference
 [1] A proteome-wide, quantitative survey of in vivo ubiquitylation sites reveals widespread regulatory roles.
 Wagner SA, Beli P, Weinert BT, Nielsen ML, Cox J, Mann M, Choudhary C.
 Mol Cell Proteomics. 2011 Oct;10(10):M111.013284. [PMID: 21890473]
 [2] hCKSAAP_UbSite: improved prediction of human ubiquitination sites by exploiting amino acid pattern and properties.
 Chen Z, Zhou Y, Song J, Zhang Z.
 Biochim Biophys Acta. 2013 Aug;1834(8):1461-7. [PMID: 23603789]
 [3] Systematic and quantitative assessment of the ubiquitin-modified proteome.
 Kim W, Bennett EJ, Huttlin EL, Guo A, Li J, Possemato A, Sowa ME, Rad R, Rush J, Comb MJ, Harper JW, Gygi SP.
 Mol Cell. 2011 Oct 21;44(2):325-40. [PMID: 21906983] 
Functional Description
 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. 
Sequence Annotation
 DOMAIN 3 133 PH.
 DOMAIN 214 274 SH3.
 DOMAIN 281 377 SH2.
 DOMAIN 402 655 Protein kinase.
 ZN_FING 135 171 Btk-type.
 NP_BIND 408 416 ATP (By similarity).
 REGION 12 24 Inositol-(1,3,4,5)-tetrakisphosphate 1-
 REGION 474 479 Inhibitor-binding.
 MOTIF 581 588 CAV1-binding.
 ACT_SITE 521 521 Proton acceptor (By similarity).
 METAL 143 143 Zinc.
 METAL 154 154 Zinc.
 METAL 155 155 Zinc.
 METAL 165 165 Zinc.
 BINDING 26 26 Inositol-(1,3,4,5)-tetrakisphosphate.
 BINDING 28 28 Inositol-(1,3,4,5)-tetrakisphosphate.
 BINDING 39 39 Inositol-(1,3,4,5)-tetrakisphosphate.
 BINDING 53 53 Inositol-(1,3,4,5)-tetrakisphosphate; via
 BINDING 430 430 ATP (By similarity).
 BINDING 445 445 Inhibitor.
 BINDING 461 461 Inhibitor.
 BINDING 477 477 Inhibitor.
 BINDING 538 538 Inhibitor.
 BINDING 539 539 Inhibitor; via amide nitrogen.
 BINDING 542 542 Inhibitor; via carbonyl oxygen.
 MOD_RES 2 2 N-acetylalanine.
 MOD_RES 21 21 Phosphoserine.
 MOD_RES 40 40 Phosphotyrosine (By similarity).
 MOD_RES 55 55 Phosphoserine.
 MOD_RES 115 115 Phosphoserine.
 MOD_RES 180 180 Phosphoserine; by PKC/PRKCB.
 MOD_RES 191 191 Phosphothreonine.
 MOD_RES 223 223 Phosphotyrosine; by autocatalysis.
 MOD_RES 344 344 Phosphotyrosine (By similarity).
 MOD_RES 361 361 Phosphotyrosine.
 MOD_RES 551 551 Phosphotyrosine; by LYN and SYK.
 MOD_RES 617 617 Phosphotyrosine.
 MOD_RES 623 623 Phosphoserine.
 MOD_RES 659 659 Phosphoserine.  
Keyword
 3D-structure; Acetylation; Adaptive immunity; Apoptosis; ATP-binding; Cell membrane; Complete proteome; Cytoplasm; Direct protein sequencing; Disease mutation; Immunity; Innate immunity; Kinase; Lipid-binding; Membrane; Metal-binding; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; Reference proteome; SH2 domain; SH3 domain; Transcription; Transcription regulation; Transferase; Tyrosine-protein kinase; Zinc; Zinc-finger. 
Sequence Source
 UniProt (SWISSPROT/TrEMBL); GenBank; EMBL 
Protein Length
 659 AA 
Protein Sequence
MAAVILESIF LKRSQQKKKT SPLNFKKRLF LLTVHKLSYY EYDFERGRRG SKKGSIDVEK 60
ITCVETVVPE KNPPPERQIP RRGEESSEME QISIIERFPY PFQVVYDEGP LYVFSPTEEL 120
RKRWIHQLKN VIRYNSDLVQ KYHPCFWIDG QYLCCSQTAK NAMGCQILEN RNGSLKPGSS 180
HRKTKKPLPP TPEEDQILKK PLPPEPAAAP VSTSELKKVV ALYDYMPMNA NDLQLRKGDE 240
YFILEESNLP WWRARDKNGQ EGYIPSNYVT EAEDSIEMYE WYSKHMTRSQ AEQLLKQEGK 300
EGGFIVRDSS KAGKYTVSVF AKSTGDPQGV IRHYVVCSTP QSQYYLAEKH LFSTIPELIN 360
YHQHNSAGLI SRLKYPVSQQ NKNAPSTAGL GYGSWEIDPK DLTFLKELGT GQFGVVKYGK 420
WRGQYDVAIK MIKEGSMSED EFIEEAKVMM NLSHEKLVQL YGVCTKQRPI FIITEYMANG 480
CLLNYLREMR HRFQTQQLLE MCKDVCEAME YLESKQFLHR DLAARNCLVN DQGVVKVSDF 540
GLSRYVLDDE YTSSVGSKFP VRWSPPEVLM YSKFSSKSDI WAFGVLMWEI YSLGKMPYER 600
FTNSETAEHI AQGLRLYRPH LASEKVYTIM YSCWHEKADE RPTFKILLSN ILDVMDEES 659 
Gene Ontology
 GO:0031410; C:cytoplasmic vesicle; IEA:Compara.
 GO:0005829; C:cytosol; IDA:UniProtKB.
 GO:0045121; C:membrane raft; IDA:HGNC.
 GO:0005634; C:nucleus; TAS:UniProtKB.
 GO:0005886; C:plasma membrane; IDA:UniProtKB.
 GO:0005524; F:ATP binding; TAS:HGNC.
 GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
 GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; TAS:UniProtKB.
 GO:0005547; F:phosphatidylinositol-3,4,5-trisphosphate binding; IDA:UniProtKB.
 GO:0002250; P:adaptive immune response; TAS:UniProtKB.
 GO:0097190; P:apoptotic signaling pathway; TAS:ProtInc.
 GO:0042113; P:B cell activation; TAS:UniProtKB.
 GO:0050853; P:B cell receptor signaling pathway; TAS:UniProtKB.
 GO:0019722; P:calcium-mediated signaling; TAS:HGNC.
 GO:0048469; P:cell maturation; IEA:Compara.
 GO:0007249; P:I-kappaB kinase/NF-kappaB cascade; IEA:Compara.
 GO:0045087; P:innate immune response; TAS:UniProtKB.
 GO:0007498; P:mesoderm development; TAS:ProtInc.
 GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
 GO:0018108; P:peptidyl-tyrosine phosphorylation; IEA:Compara.
 GO:0045579; P:positive regulation of B cell differentiation; TAS:UniProtKB.
 GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; TAS:UniProtKB.
 GO:0002902; P:regulation of B cell apoptotic process; TAS:UniProtKB.
 GO:0002721; P:regulation of B cell cytokine production; TAS:UniProtKB.
 GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
 GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
 GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
 GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
 GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW. 
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. 
Pfam
 PF00779; BTK
 PF00169; PH
 PF07714; Pkinase_Tyr
 PF00017; SH2
 PF00018; SH3_1 
SMART
 SM00107; BTK
 SM00233; PH
 SM00252; SH2
 SM00326; SH3
 SM00219; TyrKc 
PROSITE
 PS50003; PH_DOMAIN
 PS00107; PROTEIN_KINASE_ATP
 PS50011; PROTEIN_KINASE_DOM
 PS00109; PROTEIN_KINASE_TYR
 PS50001; SH2
 PS50002; SH3
 PS51113; ZF_BTK 
PRINTS
 PR00401; SH2DOMAIN.
 PR00452; SH3DOMAIN.
 PR00402; TECBTKDOMAIN.
 PR00109; TYRKINASE.