Identification of novel pleckstrin homology (PH) domains provides a hypothesis for PH domain function

Pleckstrin homology (PH) domains are difficult to find in protein sequence databases with widely used computer programs. A simple program developed to overcome this difficulty identified three proteins containing previously unrecognized PH domains; the beta-adrenergic receptor kinase (beta-ARK), the tecA protein kinase and the insulin receptor substrate protein IRS-1. The region of beta-ARK containing the novel PH domain coincides with that previously shown to bind the beta gamma subunits of trimeric G-proteins, suggesting a general hypothesis for PH domain function. PH domains were then found at the N-termini of the tecA homologues Btk and itk. In line with the hypothesis a point mutation in the PH domain of Btk is associated with defects in signal transduction.