Structural study on mutant α-L-iduronidases:: insight into mucopolysaccharidosis type I
Structural study on mutant α-L-iduronidases:: insight into mucopolysaccharidosis type I
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DOI：
10.1007/s10038-008-0272-4
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发表时间：
2008-05-01
影响因子：
3.5
通讯作者：
Sakuraba, Hitoshi
中科院分区：
文献类型：
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作者：
Sugawara, Kanako;Saito, Seiji;Sakuraba, Hitoshi
为了阐明 I 型粘多糖贮积症 (MPS I) 的基础，我们构建了突变型 α-L-艾杜糖醛酸酶 (IDUA) 的结构模型，该模型由导致 MPS I 的 33 个氨基酸取代（17 个严重、8 个中度和 8 个减弱）产生。然后，我们通过计算受影响的原子数来检查酶蛋白的结构变化，并确定均方根距离 (RMSD) 和溶剂可及表面积 (ASA)。在严重 MPS I 组中，受突变影响的原子数量和平均 RMSD 值均大于减毒组，并且与减毒组相比，与严重组中鉴定的突变相关的残基往往比减毒组更不易被溶剂接近。临床中间表型组的受影响原子数、RMSD 和 ASA 在严重组和减毒组之间表现出中间值。结果表明，重度MPS I组的核心区域发生了较大的结构变化，而减毒MPS I组的分子表面发生了较小的结构变化。彩色成像揭示了MPS I代表性突变引起的结构变化的分布和程度。因此，结构分析有助于阐明MPS I的基础。由于重度MPS I组和减毒组之间的IDUA结构变化存在差异，除了少数突变外，结构分析可以帮助预测疾病的临床结果。
To elucidate the basis of mucopolysaccharidosis type I (MPS I), we constructed structural models of mutant alpha-L-iduronidases (IDUAs) resulting from 33 amino acid substitutions that lead to MPS I (17 severe, eight intermediate, and eight attenuated). Then, we examined the structural changes in the enzyme protein by calculating the number of atoms affected and determined the root-mean-square distance (RMSD) and the solvent-accessible surface area (ASA). In the severe MPS I group, the number of atoms influenced by a mutation and the average RMSD value were larger than those in the attenuated group, and the residues associated with the mutations identified in the severe group tended to be less solvent accessible than those in the attenuated group. The clinically intermediate phenotype group exhibited intermediate values for the numbers of atoms affected, RMSD, and ASA between those in the severe group and those in the attenuated group. The results indicated that large structural changes had occurred in the core region in the severe MPS I group and small ones on the molecular surface in the attenuated MPS I group. Color imaging revealed the distributions and degrees of the structural changes caused by representative mutations for MPS I. Thus, structural analysis is useful for elucidating the basis of MPS I. As there was a difference in IDUA structural change between the severe MPS I group and the attenuated one, except for a couple of mutations, structural analysis can help predict the clinical outcome of the disease.