Structural basis for pleckstrin homology domain mutations in X-linked agammaglobulinemia.
Article Details
- CitationCopy to clipboard
Vihinen M, Zvelebil MJ, Zhu Q, Brooimans RA, Ochs HD, Zegers BJ, Nilsson L, Waterfield MD, Smith CI
Structural basis for pleckstrin homology domain mutations in X-linked agammaglobulinemia.
Biochemistry. 1995 Feb 7;34(5):1475-81.
- PubMed ID
- 7849006 [ View in PubMed]
- Abstract
Deficiencies in a tyrosine kinase, designated Btk, cause X-linked agammaglobulinemia (XLA) in man, a hereditary defect of B-cell differentiation. 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 new mutations, T33P and V64F, are presented. Btk is thus far the only protein in which mutations of the PH domain have been found to cause a disease. The three-dimensional structure of the Btk PH domain was modeled on the basis of the dynamin PH structure. Despite a relatively low sequence similarity the Btk PH domain seems to have the same two beta-sheet structure observed in the known structures. The model was used to interpret the structural basis for disease in five independent point mutations 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.