Mutations in the low-density lipoprotein receptor (LDLR), which cause familial hypercholesterolemia (FH), present a variable clinical FH phenotype. To date, over 1600 FH-causing mutations have been found worldwide. The aim of this study was to investigate the structure–function relationships of LDLR mutations by using homology modeling. Structural analysis of 36 missense mutations of known receptor activity (33 severe, 1 mild, and 2 non-pathogenic phenotypes) using sequence comparison and homology modeling was performed. Severe phenotypes had less than 2% to 32% of residual LDLR activity. Mild phenotypes had 76–92% of residual LDLR activity. Finally, non-pathogenic phenotypes had normal residual LDLR activity. Sequence comparisons showed that most of the severe phenotypes were located within the fully conserved residues of LDLR, while most of the mild and non-pathogenic phenotypes were located within the poorly conserved residues. Homology modeling demonstrated several phenomena for severe phenotypes: disruption of disulfide bond formation, disturbance of the calcium binding sites, and perturbation of LDLR hydrophobic conserved packing. In contrast, mild and non-pathogenic phenotypes did not disturb the critical region of LDLR. In addition, the root mean square deviation (RMSD) values of severe phenotype tended to be higher than the mild and non-pathogenic phenotypes, and the mean of solvent accessible surface area (ASA) of the residues in wild type structure for the severe phenotype was lower than mild and non-pathogenic phenotypes. These findings provide a better understanding in the structure–function relationships of LDLR mutations and may be useful in predicting FH severity based on future genotyping.

中文翻译：

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使用同源建模的LDL受体错义突变的结构-功能关系。

低密度脂蛋白受体（LDLR）的突变会导致家族性高胆固醇血症（FH），其临床FH表型可变。迄今为止，全世界已经发现了1600多个引起FH的突变。本研究的目的是研究LDLR的结构-功能关系使用同源性建模进行突变。使用序列比较和同源性建模对已知受体活性的36个错义突变（33个严重，1个轻度和2个非病原性表型）进行结构分析。严重的表型具有少于2％至32％的残留LDLR活性。轻度表型具有LDLR残留活性的76–92％。最后，非致病性表型具有正常的残留LDLR活性。序列比较显示，大多数严重表型位于LDLR的完全保守残基内，而大多数轻度和非致病性表型位于较差保守的残基内。同源性建模证明了严重表型的几种现象：二硫键形成的破坏，钙结合位点的破坏以及LDLR疏水性保守填料的扰动。相反，轻度和非致病性表型不会干扰LDLR的关键区域。此外，严重表型的均方根偏差（RMSD）值往往高于轻度和非致病性表型，并且野生型结构中残留的溶剂可及表面积（ASA）的平均值为严重表型低于轻度和非致病性表型。这些发现为人们对结构与功能之间的关系提供了更好的理解。严重表型的野生型结构中残基的溶剂可及表面积（ASA）的平均值低于轻度和非致病性表型。这些发现为人们对结构与功能之间的关系提供了更好的理解。严重表型的野生型结构中残基的溶剂可及表面积（ASA）的平均值低于轻度和非致病性表型。这些发现为人们对结构与功能之间的关系提供了更好的理解。LDLR突变，可用于根据未来的基因分型预测FH严重程度。