Structure of the PH domain and Btk motif from Bruton's tyrosine kinase: molecular explanations for X-linked agammaglobulinaemia.
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.
Hyvönen
M
M
European Molecular Biology Laboratory, Heidelberg, Germany.
Saraste
M
M
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000361:Agammaglobulinemia / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D001798:Blood Proteins / Q000737:chemistry; D018360:Crystallography, X-Ray; D008040:Genetic Linkage; D006801:Humans; D007091:Image Processing, Computer-Assisted; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins; D017433:Protein Structure, Secondary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014960:X Chromosome
D001798:Blood Proteins; D010750:Phosphoproteins; C039077:platelet protein P47; D015544:Inositol 1,4,5-Trisphosphate; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human