Crystal structure of Bruton's tyrosine kinase domain suggests a novel pathway for activation and provides insights into the molecular basis of X-linked agammaglobulinemia

Bruton's tyrosine kinase is intimately involved in signal transduction path ways regulating survival, activation, proliferation, and differentiation of B lineage lymphoid cells. Mutations in the human btk gene are the cause of X-linked agammaglobulinemia, a male immune deficiency disorder characteriz ed by a lack of mature, immunoglobulin-producing B lymphocytes. We have det ermined the x-ray crystal structure of the Bruton's tyrosine kinase kinase domain in its unphosphorylated state to a 2.1 Angstrom resolution. A compar ison with the structures of other tyrosine kinases and a possible mechanism of activation unique to Bruton's tyrosine kinase are provided.