Molecular modeling of the Jak3 kinase domains and structural basis for severe combined immunodeficiency

Hereditary severe combined immunodeficiency (SCID) includes a heterogeneous group of diseases that profoundly affect both cellular and humoral immune responses and require treatment by bone marrow transplantation. Characteriz ation of the cellular and molecular bases of SCID is essential to provide a ccurate genetic counseling and prenatal diagnosis, and it may offer the gro unds for alternative forms of treatment. The Jak3 gene is mutated in most c ases of autosomal recessive T-B+ SCID in humans. Jak3 belongs to the family of intracellular Janus tyrosine kinases. It is physically and functionally coupled to the common gamma chain, gamma c, shared by several cytokine rec eptors. We have established the JAK3base registry for disease and mutation information. In order to study the structural consequences of the Jak3 muta tions, the structure of the human Jak3 kinase and pseudokinase domains was modeled. Residues involved in ATP and Mg2+ binding were highly conserved in the kinase domain whereas the substrate binding region is somewhat differe nt compared to other kinases. We have identified the first naturally occurr ing mutations disrupting the function of the human Jak3 kinase domain. The structural basis of all of the known Jak3 mutations reported so far is disc ussed based on the modeled structure. The model of the Jak3 protein also pe rmits us to study Jak3 phosphorylation at the structural level and may thus serve in the design of novel immune suppressive drugs. (C) 2000 Academic P ress.