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Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability

Cataract, opacity of the eye lens, is the leading cause of visual impairment worldwide. The crucial pathogenic factors that cause cataract are misfolding and aggregation of crystallin protein. βB1‐crystallin, which is the most abundant water‐soluble protein in mammalian lens, is essential for lens t...

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Autores principales: Ren, Ling, Hu, Lidan, Zhang, Ying, Liu, Jian, Xu, Wanyue, Wu, Wei, Xu, Jingjie, Chen, Xiangjun, Yao, Ke, Yu, Yibo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964140/
https://www.ncbi.nlm.nih.gov/pubmed/35359596
http://dx.doi.org/10.3389/fmolb.2022.844719
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author Ren, Ling
Hu, Lidan
Zhang, Ying
Liu, Jian
Xu, Wanyue
Wu, Wei
Xu, Jingjie
Chen, Xiangjun
Yao, Ke
Yu, Yibo
author_facet Ren, Ling
Hu, Lidan
Zhang, Ying
Liu, Jian
Xu, Wanyue
Wu, Wei
Xu, Jingjie
Chen, Xiangjun
Yao, Ke
Yu, Yibo
author_sort Ren, Ling
collection PubMed
description Cataract, opacity of the eye lens, is the leading cause of visual impairment worldwide. The crucial pathogenic factors that cause cataract are misfolding and aggregation of crystallin protein. βB1‐crystallin, which is the most abundant water‐soluble protein in mammalian lens, is essential for lens transparency. A previous study identified the missense mutation βB1‐S93R being responsible for congenital cataract. However, the exact pathogenic mechanism causing cataract remains unclear. The S93 residue, which is located at the first Greek‐key motif of βB1‐crystallin, is highly conserved, and its substitution to Arginine severely impaired hydrogen bonds and structural conformation, which were evaluated via Molecular Dynamic Simulation. The βB1‐S93R was also found to be prone to aggregation in both human cell lines and Escherichia coli. Then, we isolated the βB1‐S93R variant from inclusion bodies by protein renaturation. The βB1-S93R mutation exposed more hydrophobic residues, and the looser structural mutation was prone to aggregation. Furthermore, the S93R mutation reduced the structural stability of βB1-crystallin when incubated at physiological temperature and made it more sensitive to environmental stress, such as UV irradiation or oxidative stress. We also constructed a βB1-S93R cellular model and discovered that βB1-S93R was more sensitive to environmental stress, causing not only aggregate formation but also cellular apoptosis and impaired cellular viability. All of the results indicated that lower solubility and structural stability, sensitivity to environmental stress, vulnerability to aggregation, and impaired cellular viability of βB1-S93R might be involved in cataract development.
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spelling pubmed-89641402022-03-30 Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability Ren, Ling Hu, Lidan Zhang, Ying Liu, Jian Xu, Wanyue Wu, Wei Xu, Jingjie Chen, Xiangjun Yao, Ke Yu, Yibo Front Mol Biosci Molecular Biosciences Cataract, opacity of the eye lens, is the leading cause of visual impairment worldwide. The crucial pathogenic factors that cause cataract are misfolding and aggregation of crystallin protein. βB1‐crystallin, which is the most abundant water‐soluble protein in mammalian lens, is essential for lens transparency. A previous study identified the missense mutation βB1‐S93R being responsible for congenital cataract. However, the exact pathogenic mechanism causing cataract remains unclear. The S93 residue, which is located at the first Greek‐key motif of βB1‐crystallin, is highly conserved, and its substitution to Arginine severely impaired hydrogen bonds and structural conformation, which were evaluated via Molecular Dynamic Simulation. The βB1‐S93R was also found to be prone to aggregation in both human cell lines and Escherichia coli. Then, we isolated the βB1‐S93R variant from inclusion bodies by protein renaturation. The βB1-S93R mutation exposed more hydrophobic residues, and the looser structural mutation was prone to aggregation. Furthermore, the S93R mutation reduced the structural stability of βB1-crystallin when incubated at physiological temperature and made it more sensitive to environmental stress, such as UV irradiation or oxidative stress. We also constructed a βB1-S93R cellular model and discovered that βB1-S93R was more sensitive to environmental stress, causing not only aggregate formation but also cellular apoptosis and impaired cellular viability. All of the results indicated that lower solubility and structural stability, sensitivity to environmental stress, vulnerability to aggregation, and impaired cellular viability of βB1-S93R might be involved in cataract development. Frontiers Media S.A. 2022-03-14 /pmc/articles/PMC8964140/ /pubmed/35359596 http://dx.doi.org/10.3389/fmolb.2022.844719 Text en Copyright © 2022 Ren, Hu, Zhang, Liu, Xu, Wu, Xu, Chen, Yao and Yu. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Ren, Ling
Hu, Lidan
Zhang, Ying
Liu, Jian
Xu, Wanyue
Wu, Wei
Xu, Jingjie
Chen, Xiangjun
Yao, Ke
Yu, Yibo
Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability
title Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability
title_full Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability
title_fullStr Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability
title_full_unstemmed Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability
title_short Cataract-Causing S93R Mutant Destabilized Structural Conformation of βB1 Crystallin Linking With Aggregates Formation and Cellular Viability
title_sort cataract-causing s93r mutant destabilized structural conformation of βb1 crystallin linking with aggregates formation and cellular viability
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964140/
https://www.ncbi.nlm.nih.gov/pubmed/35359596
http://dx.doi.org/10.3389/fmolb.2022.844719
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