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Molecular origin of the effects of mutation on the structure and mechanical properties of human epithelial keratin K5/K14
Journal of the Mechanical Behavior of Biomedical Materials ( IF 3.3 ) Pub Date : 2021-09-02 , DOI: 10.1016/j.jmbbm.2021.104798
Chien-Yu Pan , Chia-Ching Chou

Epithelial keratin, a type of intermediate filament (IF) protein, is one of the key components in maintaining the stability of the cell nucleus in the epidermis of the skin, the largest organ in the human body. It absorbs water and withstands external pressure, affecting the structural stability and mechanical properties of the skin. Epidermolysis bullosa simplex (EBS) is a rare genetic skin disease related to genetic mutations in epithelial keratin K5/K14. The resulting structural defects can cause keratinocytes in the basal layer to become fragile and rupture when subjected to mechanical stress. Its pathological feature is that the skin and mucous membranes are extremely fragile, and wounds and blisters occur under even slight external force. In this study, we focused on the amino acid sequence of the wild-type human keratin K5/K14 and sequences with point mutations, beginning with a full atomistic model of the K5/K14 heterodimer and proceeding to the higher hierarchical structure of the tetramer model. For the heterodimer, the structures of the wild type and the mutants share a high degree of similarity, and the helical structure is preserved. Then, based on the heterodimer model, we considered the keratin tetramer model with the ID1 contact from previous experimental observations. Our results suggested that in the wild-type tetramer, the hydrogen bonds formed in the middle and contact regions provide extra stability to tetramer 2B–2B interactions during IF assembly. The probabilities of hydrogen bond formation are lower in the mutant tetramers than in the wild-type tetramer in the contact region; the point mutations do not necessarily affect the structure for dimer formation, but changes in the interactions of amino acids may affect the higher-order assembly of IFs. We observed that the structures of the tetramers with point mutations were loosely stacked, and the mechanical properties were weaker than those of the wild-type tetramer. We further compared our results with the latest experimental measurements and discussed the relationship between the genotype of EBS disease and the atomic-level mutated structures. The atomistic model allowed us to study point mutations at the molecular level. The results can be further applied to reveal the effect of point mutations on EBS disease.



中文翻译:

突变对人上皮角蛋白 K5/K14 结构和力学性能影响的分子起源

上皮角蛋白是一种中间丝 (IF) 蛋白,是维持人体最大器官皮肤表皮中细胞核稳定性的关键成分之一。它吸收水分并承受外部压力,影响皮肤的结构稳定性和机械性能。单纯性大疱性表皮松解症 (EBS) 是一种罕见的遗传性皮肤病,与上皮角蛋白 K5/K14 基因突变有关。由此产生的结构缺陷会导致基底层中的角质形成细胞在受到机械应力时变得脆弱和破裂。其病理特征是皮肤和黏膜极其脆弱,即使是轻微的外力也会出现伤口和水泡。在这项研究中,我们专注于野生型人角蛋白 K5/K14 的氨基酸序列和点突变序列,从 K5/K14 异二聚体的完整原子模型开始,到四聚体模型的更高层次结构。对于异源二聚体,野生型和突变型的结构具有高度的相似性,并且保留了螺旋结构。然后,基于异二聚体模型,我们从之前的实验观察中考虑了具有 ID1 接触的角蛋白四聚体模型。我们的结果表明,在野生型四聚体中,在中间和接触区域形成的氢键为 IF 组装过程中的四聚体 2B-2B 相互作用提供了额外的稳定性。在接触区,突变四聚体中氢键形成的概率低于野生型四聚体;点突变不一定会影响二聚体形成的结构,但氨基酸相互作用的变化可能会影响 IF 的高阶组装。我们观察到具有点突变的四聚体的结构松散堆积,机械性能弱于野生型四聚体。我们进一步将我们的结果与最新的实验测量结果进行了比较,并讨论了 EBS 疾病的基因型与原子水平突变结构之间的关系。原子模型使我们能够在分子水平上研究点突变。该结果可进一步应用于揭示点突变对 EBS 疾病的影响。但是氨基酸相互作用的变化可能会影响IFs的高阶组装。我们观察到具有点突变的四聚体的结构松散堆积,机械性能弱于野生型四聚体。我们进一步将我们的结果与最新的实验测量结果进行了比较,并讨论了 EBS 疾病的基因型与原子水平突变结构之间的关系。原子模型使我们能够在分子水平上研究点突变。该结果可进一步应用于揭示点突变对 EBS 疾病的影响。但是氨基酸相互作用的变化可能会影响IFs的高阶组装。我们观察到具有点突变的四聚体的结构松散堆积,机械性能弱于野生型四聚体。我们进一步将我们的结果与最新的实验测量结果进行了比较,并讨论了 EBS 疾病的基因型与原子水平突变结构之间的关系。原子模型使我们能够在分子水平上研究点突变。该结果可进一步应用于揭示点突变对 EBS 疾病的影响。我们进一步将我们的结果与最新的实验测量结果进行了比较,并讨论了 EBS 疾病的基因型与原子水平突变结构之间的关系。原子模型使我们能够在分子水平上研究点突变。该结果可进一步应用于揭示点突变对 EBS 疾病的影响。我们进一步将我们的结果与最新的实验测量结果进行了比较,并讨论了 EBS 疾病的基因型与原子水平突变结构之间的关系。原子模型使我们能够在分子水平上研究点突变。该结果可进一步应用于揭示点突变对 EBS 疾病的影响。

更新日期:2021-09-09
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