Structural Basis of a Point Mutation that Causes the Genetic Disease Aspartylglucosaminuria
Structural Basis of a Point Mutation that Causes the Genetic Disease Aspartylglucosaminuria
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DOI：
10.1016/j.str.2014.09.014
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发表时间：
2014-12-02
期刊：
影响因子：
5.7
通讯作者：
Guo, Hwai-Chen
中科院分区：
文献类型：
--
作者：
Sui, Lufei;Lakshminarasimhan, Damodharan;Guo, Hwai-Chen
天冬氨酸氨基葡萄糖尿症（Aspartylglucosaminuria，AGU）是由溶酶体消化天冬氨酸连接的糖蛋白的代谢紊乱引起的溶酶体储存疾病。与AGU连接的特异性酶是一种称为糖基天冬酰胺酶的溶酶体水解酶。晶体学研究表明，表面环块的成熟水解酶的催化中心。因此，需要自体蛋白水解来去除该P环并打开水解酶中心。尽管如此，AGU突变导致其前体的错误加工，并且在水解糖天冬酰胺方面存在缺陷。为了了解AGU突变的催化和结构后果，我们描述了两种AGU模型，一种对应于芬兰等位基因，另一种在加拿大家庭中发现。我们还报道了后者AGU模型的2.1埃分辨率结构。目前的晶体学研究提供了AGU突变体的高分辨率结构。它揭示了大量的构象变化，在有缺陷的自切割位点的AGU突变体，这是作为一个无活性的前体被困。
Aspartylglucosaminuria (AGU) is a lysosomal storage disease caused by a metabolic disorder of lysosomes to digest Asn-linked glycoproteins. The specific enzyme linked to AGU is a lysosomal hydrolase called glycosylasparaginase. Crystallographic studies revealed that a surface loop blocks the catalytic center of the mature hydrolase. Autoproteolysis is therefore required to remove this P loop and open up the hydrolase center. Nonetheless, AGU mutations result in misprocessing of their precursors and are deficient in hydrolyzing glycoasparagines. To understand the catalytic and structural consequences of AGU mutations, we have characterized two AGU models, one corresponding to a Finnish allele and the other found in a Canadian family. We also report a 2.1 angstrom resolution structure of the latter AGU model. The current crystallographic study provides a high-resolution structure of an AGU mutant. It reveals substantial conformation changes at the defective autocleavage site of the AGU mutant, which is trapped as an inactive precursor.