Role of the PHTH module in protein substrate recognition by Bruton's agammaglobulinemia tyrosine kinase

Defects in Bruton's tyrosine kinase (Btk) are responsible for X chromosome- linked agammaglobulinemia in patients. Mutations in each of the structural domains of Btk have been detected in patients, yet a mechanistic explanatio n for most of these mutant phenotypes is lacking. To understand the possibl e role of the unique pleckstrin homology and Tee homology (PHTH) module of Btk, we have compared the enzymatic properties of full-length Btk and a Btk mutant lacking the PHTH module (Btk Delta PHTH). Here we show that Btk and Btk Delta PHTH have similar basal catalytic activity but very different ab ilities to recognize protein substrates. Furthermore, the catalytic domain of Btk is inactive, in contrast to the catalytic domain of the prototypical Src tyrosine kinase that retains full catalytic ability. These data sugges t that the PHTH module plays an important role in protein substrate recogni tion, that. Btk and Src likely have different interdomain organizations and regulations, and that alterations in substrate recognition might play a ro le in X chromosome-linked agammaglobulinemia.