Molecular modeling of the Jak3 kinase domains and structural basis for severe combined immunodeficiency
Molecular modeling of the Jak3 kinase domains and structural basis for severe combined immunodeficiency
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DOI：
10.1006/clim.2000.4880
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发表时间：
2000-08-01
影响因子：
8.6
通讯作者：
Notarangelo, LD
中科院分区：
文献类型：
--
作者：
Vihinen, M;Villa, A;Notarangelo, LD
遗传性严重联合免疫缺陷（SCID）包括一组严重影响细胞和体液免疫应答的异质性疾病，需要通过骨髓移植进行治疗。描述SCID的细胞和分子基础对于提供准确的遗传咨询和产前诊断是必不可少的，并且它可能为替代形式的治疗提供基础。Jak 3基因在人类常染色体隐性T-B+ SCID的大多数病例中发生突变。Jak 3属于细胞内Janus酪氨酸激酶家族。它在物理和功能上与几种细胞因子受体共有的γ链γ c偶联。我们已经建立了JAK 3base登记处，用于疾病和突变信息。为了研究Jak 3突变的结构后果，对人Jak 3激酶和假激酶结构域的结构进行建模。参与ATP和Mg 2+结合的残基在激酶结构域中高度保守，而底物结合区与其他激酶相比有些不同。我们已经确定了第一个自然发生的突变破坏人类Jak 3激酶结构域的功能。迄今为止报道的所有已知的Jak 3突变的结构基础进行了讨论的基础上建模的结构。Jak 3蛋白的模型也使我们能够在结构水平上研究Jak 3的磷酸化，从而可以用于设计新的免疫抑制药物。(C)北京大学出版社.
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.