Crystal structure of the MuSK tyrosine kinase: Insights into receptor autoregulation
Crystal structure of the MuSK tyrosine kinase: Insights into receptor autoregulation
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DOI：
10.1016/s0969-2126(02)00814-6
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发表时间：
2002-09-01
期刊：
影响因子：
5.7
通讯作者：
Hubbard, SR
中科院分区：
文献类型：
--
作者：
Till, JH;Becerra, M;Hubbard, SR
肌肉特异性激酶（Muscle-specific kinase，MuSK）是一种选择性表达于骨骼肌的受体酪氨酸激酶。在神经肌肉突触形成期间，从运动神经元释放的聚集蛋白刺激激酶激活环和质膜区域中的MuSK自磷酸化，导致乙酰胆碱受体的聚集。我们已经在2.05埃分辨率下确定了未磷酸化MuSK胞质结构域的晶体结构。结构揭示了一个自抑制激酶结构域，其中激活环阻碍ATP和底物结合。稳态动力学分析表明，自磷酸化的结果在一个200倍的增加k（猫）和10倍的减少K-m ATP。这些研究为理解MuSK催化活性的调节提供了分子基础，并表明另外的体内组分可能有助于通过质膜区域进行调节。
Muscle-specific kinase (MuSK) is a receptor tyrosine kinase expressed selectively in skeletal muscle. During neuromuscular synapse formation, agrin released from motor neurons stimulates MuSK autophosphorylation in the kinase activation loop and in the juxtamembrane region, leading to clustering of acetylcholine receptors. We have determined the crystal structure of the cytoplasmic domain of unphosphorylated MuSK at 2.05 Angstrom resolution. The structure reveals an autoinhibited kinase domain in which the activation loop obstructs ATP and substrate binding. Steady-state kinetic analysis demonstrates that autophosphorylation results in a 200-fold increase in k(cat) and a 10-fold decrease in the K-m for ATP. These studies provide a molecular basis for understanding the regulation of MuSK catalytic activity and suggest that an additional in vivo component may contribute to regulation via the juxtamembrane region.