Unexpected effects of FERM domain mutations on catalytic activity of Jak3:Structural implication for Janus kinases

Janus kinases comprise carboxyterminal kinase, pseudokinase, SH2-like, and N-terminal FERM domains. We identified three patient-derived mutations in t he FERM domain of Jak3 and investigated the functional consequences of thes e mutations. These mutations inhibited receptor binding and also abrogated kinase activity, suggesting interactions between the FERM and kinase domain s. In fact, the domains were found to physically associate, and coexpressio n of the FERM domain enhanced activity of the isolated kinase domain. Conve rsely, staurosporine, which alters kinase domain structure, disrupted recep tor binding, even though the catalytic activity of Jak3 is dispensable for receptor binding. Thus, the Jak FERM domain appears to have two critical fu nctions: receptor interaction and maintenance of kinase integrity.