Structural bases of GM1 gangliosidosis and Morquio B disease
Structural bases of GM1 gangliosidosis and Morquio B disease
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GM1 神经节苷脂沉积症和 Morquio B 病的结构基础
DOI：
10.1038/jhg.2009.70
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发表时间：
2009
影响因子：
3.5
通讯作者：
H. Sakuraba
中科院分区：
文献类型：
--
作者：
Mizuki Morita;S. Saito;K. Ikeda;K. Ohno;K. Sugawara;Toshihiro Suzuki;T. Togawa;H. Sakuraba
溶酶体β-半乳糖苷酶基因的等位基因突变导致异质性临床表型，例如GM1神经节苷脂沉积症和Morquio B病，前者进一步分为三种变体，即婴儿型、青少年型和成人型；这些形式显示出异质的生化表型。我们试图从结构的角度阐明这些疾病的根源。我们首先通过同源建模的方式构建了人β-半乳糖苷酶的三维结构模型。人β-半乳糖苷酶由三个结构域组成，例如充当催化结构域的TIM桶状折叠结构域和两个半乳糖结合结构域样折叠结构域。然后，我们构建了代表性突变型β-半乳糖苷酶蛋白（G123R、R201C、I51T 和 Y83H）的结构模型，并通过计算受影响原子的数量、确定均方根偏差和溶剂可及表面积以及彩色成像来预测与每种表型相关的结构变化。结果表明，这些代表性病例中β-半乳糖苷酶分子中氨基酸取代引起的结构变化与生化和临床表型之间存在良好的相关性。蛋白质结构研究有助于阐明这些疾病的基础。
Allelic mutations of the lysosomal β-galactosidase gene cause heterogeneous clinical phenotypes, such as GM1 gangliosidosis and Morquio B disease, the former being further classified into three variants, namely infantile, juvenile and adult forms; and heterogeneous biochemical phenotypes were shown in these forms. We tried to elucidate the bases of these diseases from a structural viewpoint. We first constructed a three-dimensional structural model of human β-galactosidase by means of homology modeling. The human β-galactosidase consists of three domains, such as, a TIM barrel fold domain, which functions as a catalytic domain, and two galactose-binding domain-like fold domains. We then constructed structural models of representative mutant β-galactosidase proteins (G123R, R201C, I51T and Y83H) and predicted the structural change associated with each phenotype by calculating the number of affected atoms, determining the root-mean-square deviation and the solvent-accessible surface area, and by color imaging. The results show that there is a good correlation between the structural changes caused by amino-acid substitutions in the β-galactosidase molecule, as well as biochemical and clinical phenotypes in these representative cases. Protein structural study is useful for elucidating the bases of these diseases.