Structural basis for pleckstrin homology domain mutations in X-linked agammaglobulinemia

Research output: Contribution to journalArticle

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 P-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.

Details

Authors
  • Mauno Vihinen
  • MJJM ZVELEBIL
  • QL ZHU
  • RA BROOIMANS
  • HD OCHS
  • BJM ZEGERS
  • L NILSSON
  • MD WATERFIELD
  • CIE SMITH
External organisations
  • External Organization - Unknown
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Biochemistry and Molecular Biology
Original languageEnglish
Pages (from-to)1475-1481
JournalBiochemistry
Volume34
Issue number5
Publication statusPublished - 1995
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes