Molecular origin of the effects of mutation on the structure and mechanical properties of human epithelial keratin K5/K14
CY Pan and CC Chou, JOURNAL OF THE MECHANICAL BEHAVIOR OF BIOMEDICAL MATERIALS, 124, 104798 (2021).
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 higherorder 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.
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