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

Research output: Contribution to journalArticle


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. Characterization of the cellular and molecular bases of SCID is essential to provide accurate genetic counseling and prenatal diagnosis, and it may offer the grounds for alternative forms of treatment. The Jak3 gene is mutated in most cases 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 receptors. We have established the JAK3base registry for disease and mutation information. In order to study the structural consequences of the Jak3 mutations, 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 different compared to other kinases. We have identified the first naturally occurring mutations disrupting the function of the human Jak3 kinase domain. The structural basis of all of the known Jak3 mutations reported so far is discussed based on the modeled structure. The model of the Jak3 protein also permits us to study Jak3 phosphorylation at the structural level and may thus serve in the design of novel immune suppressive drugs. (C) 2000 Academic Press.


  • Mauno Vihinen
  • A Villa
  • P Mella
  • RF Schumacher
  • G Savoldi
  • JJ O'Shea
  • F Candotti
  • LD Notarangelo
External organisations
  • External Organization - Unknown
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area


  • immunodeficiency, B cells, T cells, disease-causing mutations, structural basis of disease, structure-function relationships, JAK3base
Original languageEnglish
Pages (from-to)108-118
JournalClinical Immunology
Issue number2
Publication statusPublished - 2000
Publication categoryResearch
Externally publishedYes