Crystal structure of the agrin-responsive immunoglobulin-like domains 1 and 2 of the receptor tyrosine kinase MuSK
Crystal structure of the agrin-responsive immunoglobulin-like domains 1 and 2 of the receptor tyrosine kinase MuSK
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DOI：
10.1016/j.jmb.2006.09.019
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发表时间：
2006-12-01
影响因子：
5.6
通讯作者：
Hubbard, Stevan R.
中科院分区：
文献类型：
--
作者：
Stiegler, Amy L.;Burden, Steven J.;Hubbard, Stevan R.
肌肉特异性激酶(Musk)是一种仅在骨骼肌中表达的受体酪氨酸激酶，它是形成神经肌肉接头所必需的。麝香被集聚蛋白激活，集聚蛋白是一种神经元衍生的硫酸乙酰肝素蛋白多糖。在这里，我们报告了在2.2埃分辨率下麝香胞外结构域的集聚反应第一和第二免疫球蛋白样域(IG1和IG2)的晶体结构。结构表明，Musk IGI和IG2是I-SET亚家族的Ig样结构域，以线性、半刚性排列方式配置。除了典型的内部二硫键外，IG1还含有第二个暴露在溶剂中的二硫键，我们的生化数据表明，这对IGI的正确折叠和麝香的加工至关重要。两个IG1-2分子形成非晶体二聚体，该二聚体由IG1表面独特的疏水斑块介导。将麝香突变体导入到麝香(-/-)肌管中的生化分析表明，这种疏水斑块中的残基对于集聚蛋白诱导的麝香激活至关重要。(C)2006爱思唯尔有限公司。保留所有权利。
Muscle-specific kinase (MuSK) is a receptor tyrosine kinase expressed exclusively in skeletal muscle, where it is required for formation of the neuromuscular junction. MuSK is activated by agrin, a neuron-derived heparan sulfate proteoglycan. Here, we report the crystal structure of the agrin-responsive first and second immunoglobulin-like domains (Ig1 and Ig2) of the MuSK ectodomain at 2.2 angstrom resolution. The structure reveals that MuSK IgI and Ig2 are Ig-like domains of the I-set subfamily, which are configured in a linear, semi-rigid arrangement. In addition to the canonical internal disulfide bridge, Ig1 contains a second, solvent-exposed disulfide bridge, which our biochemical data indicate is critical for proper folding of IgI and processing of MuSK. Two Ig1-2 molecules form a non-crystallographic dimer that is mediated by a unique hydrophobic patch on the surface of Ig1. Biochemical analyses of MuSK mutants introduced into MuSK(-/-) myotubes demonstrate that residues in this hydrophobic patch are critical for agrin-induced MuSK activation. (c) 2006 Elsevier Ltd. All rights reserved.