Structural Analysis of Janus Kinases.

Janus Kinase 3 (Jak3) plays an essential role in hematopoietic signaling. Primarily expressed in B-, T- and Natural killer cells, it is activated through the γc chain of interleukin-2 like cytokine receptors (IL-2, -4, -7, -9, -15, -21). Deficiency of catalytically active Jak3 or disruption of the Jak3:IL-2γc interaction results in severe combined immunodeficiency (SCID). Jak3-deficient humans demonstrate defects restricted to the immune system, suggesting that selective inhibition of Jak3 catalytic activity or interruption of the Jak3:IL-2γc interaction are potentially exploitable strategies to achieve immunosuppression. Jak kinases contain four defined regions; a catalytically active carboxy-terminal kinase, a pseudo-kinase, a SH2-like region and a N-terminal Ferm domain. To date, no direct structural information has been reported for portions of any of the Jak family kinases. Structural studies are underway to define crystallographically the kinase domain of Jak3 and the Jak3-Ferm:IL-2γc interaction. Structural insights into the mechanism of Jak activation and routes to specific inhibition will be discussed.