Advanced

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

Vihinen, Mauno LU ; Villa, A; Mella, P; Schumacher, RF; Savoldi, G; O'Shea, JJ; Candotti, F and Notarangelo, LD (2000) In Clinical Immunology 96(2). p.108-118
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
immunodeficiency, B cells, T cells, disease-causing mutations, structural basis of disease, structure-function relationships, JAK3base
in
Clinical Immunology
volume
96
issue
2
pages
108 - 118
publisher
Elsevier
external identifiers
  • wos:000088615500007
  • scopus:0033859365
ISSN
1521-6616
DOI
10.1006/clim.2000.4880
language
English
LU publication?
no
id
392b66de-3d84-4575-b661-30a6082ea78e (old id 3852019)
date added to LUP
2013-06-28 15:29:44
date last changed
2017-01-01 04:23:20
@article{392b66de-3d84-4575-b661-30a6082ea78e,
  abstract     = {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.},
  author       = {Vihinen, Mauno and Villa, A and Mella, P and Schumacher, RF and Savoldi, G and O'Shea, JJ and Candotti, F and Notarangelo, LD},
  issn         = {1521-6616},
  keyword      = {immunodeficiency,B cells,T cells,disease-causing mutations,structural basis of disease,structure-function relationships,JAK3base},
  language     = {eng},
  number       = {2},
  pages        = {108--118},
  publisher    = {Elsevier},
  series       = {Clinical Immunology},
  title        = {Molecular modeling of the Jak3 kinase domains and structural basis for severe combined immunodeficiency},
  url          = {http://dx.doi.org/10.1006/clim.2000.4880},
  volume       = {96},
  year         = {2000},
}