Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2008) Nucleic Acids Res , doi:10.1093/nar/gkn808

• HOME
• SETUP
• FAQ
• ABOUT
• GLOSSARY
• WHAT'S NEW
• FEEDBACK

BTK Bruton's tyrosine kinase Cys-rich motif

There are 228 BTK domains in 227 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a BTK domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with BTK domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Anopheles gambiae, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Takifugu rubripes

• Cellular role (predicted cellular role)

• Binding / catalysis: zinc-binding

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Vihinen M et al.
  • BTKbase, mutation database for X-linked agammaglobulinemia (XLA).
  • Nucleic Acids Res. 1998; 26: 242-7
  • Display abstract

  • X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations has been compiled and the recent update lists 463 mutation entries from 406 unrelated families showing 303 unique molecular events. In addition to mutations, the database also lists variants or polymorphisms. Each patient is given a unique patient identity number (PIN). Information is included regarding the phenotype including symptoms. Mutations in all the five domains of BTK have been noticed to cause the disease, the most common event being missense mutations. The mutations appear almost uniformly throughout the molecule and frequently affect CpG sites that code for arginine residues. The putative structural implications of all the missense mutations are given in the database. The improved version of the registry having a number of new features is available at http://www. helsinki.fi/science/signal/btkbase.html

  • Desiderio S
  • Role of Btk in B cell development and signaling.
  • Curr Opin Immunol. 1997; 9: 534-40
  • Display abstract

  • Bruton's tyrosine kinase (Btk), the target of inactivating mutations in X-linked immunodeficiency diseases of mice and humans, is essential for normal B cell responsiveness. Recent studies have outlined a mechanism for the activation of Btk by B cell receptor engagement and have identified proximal and distal targets of Btk action.

  • Hyvonen M, Saraste M
  • Structure of the PH domain and Btk motif from Bruton's tyrosine kinase: molecular explanations for X-linked agammaglobulinaemia.
  • EMBO J. 1997; 16: 3396-404
  • Display abstract

  • Bruton's tyrosine kinase (Btk) is an enzyme which is involved in maturation of B cells. It is a target for mutations causing X-linked agammaglobulinaemia (XLA) in man. We have determined the structure of the N-terminal part of Btk by X-ray crystallography at 1.6 A resolution. This part of the kinase contains a pleckstrin homology (PH) domain and a Btk motif. The structure of the PH domain is similar to those published previously: a seven-stranded bent beta-sheet with a C-terminal alpha-helix. Individual point mutations within the Btk PH domain which cause XLA can be classified as either structural or functional in the light of the three-dimensional structure and biochemical data. All functional mutations cluster into the positively charged end of the molecule around the predicted binding site for phosphatidylinositol lipids. It is likely that these mutations inactivate the Btk pathway in cell signalling by reducing its affinity for inositol phosphates, which causes a failure in translocation of the kinase to the cell membrane. A small number of signalling proteins contain a Btk motif that always follows a PH domain in the sequence. This small module has a novel fold which is held together by a zinc ion bound by three conserved cysteines and a histidine. The Btk motif packs against the second half of the beta-sheet of the PH domain, forming a close contact with it. Our structure opens up new ways to study the role of the PH domain and Btk motif in the cellular function of Btk and the molecular basis of its dysfunction in XLA patients.

  • Vihinen M et al.
  • Missense mutations affecting a conserved cysteine pair in the TH domain of Btk.
  • FEBS Lett. 1997; 413: 205-10
  • Display abstract

  • Tec family protein tyrosine kinases have in their N-terminus two domains. The PH domain is followed by Tec homology (TH) domain, which consists of two motifs. The first pattern, Btk motif, is also present in some Ras GAP molecules. C-terminal half of the TH domain, a proline-rich region, has been shown to bind to SH3 domains. Mutations in Bruton's tyrosine kinase (Btk) belonging to the Tec family cause X-linked agammaglobulinemia (XLA) due to developmental arrest of B cells. Here we present the first missense mutations in the TH domain. The substitutions affect a conserved pair of cysteines, residues 154 and 155, involved in Zn2+ binding and thereby the mutations alter protein folding and stability.

  • Vihinen M, Nilsson L, Smith CI
  • Tec homology (TH) adjacent to the PH domain.
  • FEBS Lett. 1994; 350: 263-5
  • Display abstract

  • The pleckstrin homology (PH) domain 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. The TH domain contains a conserved 27 amino acid stretch designated the Btk motif and a proline-rich region. Sequence similarity was found to a putative Ras GTPase activating protein and a human interferon-gamma binding protein both in the PH domain and the Btk motif region. SLK1/SSP31 protein kinase and a non-catalytic p85 subunit of PI-3 kinase had similarity only with the proline rich region. The identification of a PH domain extension in some signal transduction proteins in different species suggests that this region is involved in protein-protein interactions.

• Disease (disease genes where sequence variants are found in this domain)

• SwissProt sequences and OMIM curated human diseases associated with missense mutations within the BTK domain.

  Protein	Disease
  Tyrosine-protein kinase BTK (SRS)(SMART)	OMIM:300300: Agammaglobulinemia, type 1, X-linked ; ?XLA and isolated growth hormone deficiency OMIM:307200:

• Metabolism (metabolic pathways involving proteins which contain this domain)

• % proteins involved KEGG pathway ID Description 33.33 map04660 T cell receptor signaling pathway 17.78 map04010 MAPK signaling pathway 17.78 map04670 Leukocyte transendothelial migration 15.56 map04664 Fc epsilon RI signaling pathway 15.56 map04662 B cell receptor signaling pathway This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with BTK domain which could be assigned to a KEGG orthologous group, and not all proteins containing BTK domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of BTK domains in PDB

  PDB code	Main view	Title
  1b55		Ph domain from bruton's tyrosine kinase in complex with inositol 1,3,4,5-tetrakisphosphate
  1btk		Ph domain and btk motif from bruton's tyrosine kinase mutant r28c
  1bwn		Ph domain and btk motif from bruton's tyrosine kinase mutant e41k in complex with ins(1,3,4,5)p4
  2e6i		Solution structure of the btk motif of tyrosine-protein kinase itk from human
  2ys2		Solution structure of the btk motif of human cytoplasmic tyrosine-protein kinase bmx
  2z0p		Crystal structure of ph domain of bruton's tyrosine kinase

• Links (links to other resources describing this domain)

• INTERPRO	IPR001562