STRUCTURAL BASIS FOR PLECKSTRIN HOMOLOGY DOMAIN MUTATIONS IN X-LINKEDAGAMMAGLOBULINEMIA

Deficiencies in a tyrosine kinase, designated Btk, cause X-linked agam maglobulinemia (XLA) in man, a hereditary defect of B-cell differentia tion. Mutations in the newly found PH domain located at the N-terminus of Btk have been shown to be the direct cause of XLA, and here two ne w mutations, T33P and V64F, are presented. Btk is thus far the only pr otein in which mutations of the PH domain have been found to cause a d isease. The three-dimensional structure of the Btk PH domain was model ed on the basis of the dynamin PH structure. Despite a relatively low sequence similarity the Btk PH domain seems to have the same two P-she et structure observed in the known structures. The model was used to i nterpret the structural basis for disease in five independent point mu tations and in an insertion in patients with XLA. The mutated residues F25, V64, and V113, and possibly residue(s) around Q103, could form a binding site, since these amino acids are located close to each other on the surface of the molecule.