Structural basis for chromosome X-linked agammaglobulinemia: a tyrosine kinase disease.
Vihinen M,
Vetrie D,
Maniar HS,
Ochs HD,
Zhu Q,
Vorechovský I,
Webster AD,
Notarangelo LD,
Nilsson L,
Sowadski JM, et al.
Center for Structural Biochemistry, Karolinska Institute, NOVUM, Huddinge, Sweden.
X-linked agammaglobulinemia (XLA) is a hereditary defect of B-cell differentiation in man caused by deficiency of Bruton tyrosine kinase (BTK). A three-dimensional model for the BTK kinase domain, based on the core structure of cAMP-dependent protein kinase, was used to interpret the structural basis for disease in eight independent point mutations in patients with XLA. As Arg-525 of BTK has been thought to functionally substitute for a critical lysine residue in protein-serine kinases, the mutation Arg-525-->Gln was studied and found to abrogate the tyrosine kinase activity of BTK. All of the eight mutations (Lys-430-->Glu, Arg-520-->Glu, Arg-525-->Gln, Arg-562-->Pro, Ala-582-->Val, Glu-589-->Gly, Gly-594-->Glu, and Gly-613-->Asp) were located on one face of the BTK kinase domain, indicating structural clustering of functionally important residues.
PMID: 7809124 [PubMed - indexed for MEDLINE]
PMCID: PMC45528