Structural basis for chromosome X-linked agammaglobulinemia: a tyrosine kinase disease.
Structural basis for chromosome X-linked agammaglobulinemia: a tyrosine kinase disease.
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DOI：
10.1073/pnas.91.26.12803
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发表时间：
1994-12
影响因子：
11.1
通讯作者：
M. Vihinen;D. Vetrie;H. Maniar;H. Ochs;Qili Zhu;I. Vořechovský;A. Webster;L. Notarangelo;L. Nilsson;J. Sowadski
中科院分区：
文献类型：
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作者：
M. Vihinen;D. Vetrie;H. Maniar;H. Ochs;Qili Zhu;I. Vořechovský;A. Webster;L. Notarangelo;L. Nilsson;J. Sowadski
x连锁无球蛋白血症（XLA）是一种由布鲁顿酪氨酸激酶（BTK）缺乏引起的人类b细胞分化的遗传性缺陷。基于camp依赖性蛋白激酶核心结构的BTK激酶结构域三维模型，用于解释XLA患者8个独立点突变的疾病结构基础。由于BTK的Arg-525一直被认为在功能上替代了蛋白-丝氨酸激酶中一个关键的赖氨酸残基，研究人员发现突变Arg-525- >Gln消除了BTK的酪氨酸激酶活性。所有8个突变（Lys-430—>Glu, Arg-520—>Glu, Arg-525—>Gln, Arg-562—>Pro, Ala-582—>Val, Glu-589—>Gly, Gly-594—>Glu和Gly-613—>Asp）都位于BTK激酶结构域的一个面上，表明功能重要残基的结构聚类。
X-linked agammaglobulinemia (XLA) is a hereditary defect of B-cell differentiation in man caused by deficiency of Bruton tyrosine kinase (BTK). A three-dimensional model for the BTK kinase domain, based on the core structure of cAMP-dependent protein kinase, was used to interpret the structural basis for disease in eight independent point mutations in patients with XLA. As Arg-525 of BTK has been thought to functionally substitute for a critical lysine residue in protein-serine kinases, the mutation Arg-525-->Gln was studied and found to abrogate the tyrosine kinase activity of BTK. All of the eight mutations (Lys-430-->Glu, Arg-520-->Glu, Arg-525-->Gln, Arg-562-->Pro, Ala-582-->Val, Glu-589-->Gly, Gly-594-->Glu, and Gly-613-->Asp) were located on one face of the BTK kinase domain, indicating structural clustering of functionally important residues.