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首页> 外文期刊>Journal of Molecular Biology >Analysis of disease-linked rhodopsin mutations based on structure, function, and protein stability calculations.
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Analysis of disease-linked rhodopsin mutations based on structure, function, and protein stability calculations.

机译：基于结构，功能和蛋白质稳定性计算的疾病相关视紫红质突变分析。

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Retinitis pigmentosa (RP) refers to a heterogeneous group of inherited diseases that result in progressive retinal degeneration, characterized by visual field constriction and night blindness. A total of 103 mutations in rhodopsin are linked to RP to date, and the phenotypes range from severe to asymptomatic. To study the relation between phenotype and rhodopsin stability in disease mutants, we used a structure-based approach. For 12 of the mutants located at the protein-lipid interphase, we used the von Heijne water-membrane transfer scale, and we find that 9 of the mutations could affect membrane insertion. For 91 mutants, we used the protein design algorithm FoldX. The 3 asymptomatic mutations had no significant reduced stability, 2 were unsuitable for FoldX analysis since the structure was incorrect in this region, 63 mutations had a significant change in protein stability (>1.6 kcal/mol), and 23 mutations had energy change values under the prediction error threshold (<1.6 kcal/mol). Out of these 23, the disease-causing effect could be explained by the involvement in other functions (e.g., glycosylation motifs, the interface with arrestin and transducin, and the cilia-binding motif) for 19 mutants. The remaining 4 mutants were probably incorrectly associated with RP or have functionalities not discovered yet. For destabilizing mutations where clinical data were available, we found a highly significant correlation between FoldX energy changes and the average age of night blindness and between FoldX energy changes and daytime vision loss onset. Our detailed structural, functional, and energetic analysis provides a complete picture of the rhodopsin mutations and can guide mutation-specific therapies.
机译：色素性视网膜炎（RP）是指导致疾病进行性视网膜变性的异质性遗传疾病，其特征在于视野狭窄和夜盲。迄今为止，视紫红质中共有103个突变与RP相关，其表型从严重到无症状。为了研究疾病突变体表型与视紫红质稳定性之间的关系，我们使用了基于结构的方法。对于位于蛋白-脂质界面的12个突变体，我们使用了von Heijne水-膜转移规模，我们发现其中9个突变体会影响膜的插入。对于91个突变体，我们使用了蛋白质设计算法FoldX。 3个无症状突变没有显着降低的稳定性，2个不适合FoldX分析，因为该区域的结构不正确，63个突变具有显着的蛋白质稳定性变化（> 1.6 kcal / mol），23个突变的能量变化值低于预测误差阈值（<1.6 kcal / mol）。在这23种中，致病作用可以通过涉及19个突变体的其他功能（例如糖基化基序，与抑制素和转导蛋白的界面以及纤毛结合基序）来解释。其余4个突变体可能与RP错误相关或尚未发现功能。对于可获得临床数据的不稳定突变，我们发现FoldX能量变化与夜盲的平均年龄之间以及FoldX能量变化与白天视力丧失之间存在高度显着的相关性。我们详细的结构，功能和能量分析提供了视紫红质突变的完整图片，并可以指导突变特异性疗法。

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