βB2 W151R mutant is prone to degradation, aggregation and exposes the hydrophobic side chains in the fourth Greek Key motif

Xu, Junjie; Wang, Huaxia; Wang, Ailing; Xu, Jia; Fu, Chenxi; Jia, Zhaobao; Yao, Ke; Chen, Xiangjun

doi:10.1016/j.bbadis.2020.166018

Cited by 17 publications

(13 citation statements)

References 35 publications

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“…In line with the main findings in the Crybb2 knockout mouse, several human studies attested to the association between mutations in the βB2-crystallin locus and cataracts [68,79]. Besides a functional βB2-crystallin locus, in humans there is a second βB2-crystallin-derived pseudogene, termed CRYBB2P1.…”

Section: Ocular Pathologiesmentioning

confidence: 65%

Physiological and pathological functions of βB2-crystallins in multiple organs: a systematic review

Li¹,

Liu²,

Huang³

et al. 2021

aging

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Crystallins, the major constituent proteins of mammalian lenses, are significant not only for the maintenance of eye lens stability, transparency, and refraction, but also fulfill various physiopathological functions in extraocular tissues. βB2-crystallin, for example, is a multifunctional protein expressed in the human retina, brain, testis, ovary, and multiple tumors. Mutations in the βB2 crystallin gene or denaturation of βB2-crystallin protein are associated with cataracts, ocular pathologies, and psychiatric disorders. A prominent role for βB2crystallins in axonal growth and regeneration, as well as in dendritic outgrowth, has been demonstrated after optic nerve injury. Studies in βB2-crystallin-null mice revealed morphological and functional abnormalities in testis and ovaries, indicating βB2-crystallin contributes to male and female fertility in mice. Interestingly, although pathogenic significance remains obscure, several studies identified a clear correlation between βB2 crystallin expression and the prognosis of patients with breast cancer, colorectal cancer, prostate cancer, renal cell carcinoma, and glioblastoma in the African American population. This review summarizes the physiological and pathological functions of βB2-crystallin in the eye and other organs and tissues and discusses findings related to the expression and potential role of βB2-crystallin in tumors.

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Section: Ocular Pathologiesmentioning

confidence: 65%

Physiological and pathological functions of βB2-crystallins in multiple organs: a systematic review

Li¹,

Liu²,

Huang³

et al. 2021

aging

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“…Both cell lines were incubated in 5% CO 2 at 37°C. The WT and S93R genes were exogenously overexpressed in both cell lines to establish the cataract cell models, and the protein distribution within the cells were visualized using immunofluorescence, as previously described ( Xu et al, 2021 ). In brief, the WT and S93R-fused plasmids were transfected into the HEK 293T cells using Lipofectamine 2000 and the HLE-B3 cells were transfected using Lipofectamine 3000.…”

Section: Methodsmentioning

confidence: 99%

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

Ren

Zhang

et al. 2022

Front. Mol. Biosci.

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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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“…Structures of PMM2 and Decreased Protein Solubility. The C9Y (c. G26A) variant has been identified in at least 7 families from France, Germany, Sweden, and the USA [37,38]. The C9 was highly conserved and located near the active site Asp12, probably leading to enzymatic inactivation.…”

Section: Cys Substitution Impaired the Secondary And Tertiarymentioning

confidence: 99%

Cysteine Pathogenic Variants of PMM2 Are Sensitive to Environmental Stress with Loss of Structural Stability

Lin

Sun

et al. 2023

Oxidative Medicine and Cellular Longevity

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Congenital disorders of glycosylation (CDG) are severe metabolic disorders caused by an imbalance in the glycosylation pathway. Phosphomannomutase2 (PMM2-CDG), the most prevalent CDG, is mainly due to the disorder of PMM2. Pathogenic variants in cysteine have been found in various diseases, and cysteine residues have a potential as therapeutic targets. PMM2 harbor six cysteines; the variants Cys9Tyr (C9Y) and Cys241Ser (C241S) of PMM2 have been identified to associate with CDG, but the underlying molecular mechanisms remain uncharacterized. Here, we purified PMM2 wild type (WT), C9Y, and C241S to investigate their structural characteristics and biophysical properties by spectroscopic experiments under physiological temperature and environmental stress. Notably, the variants led to drastic changes in the protein properties and were prone to aggregate at physiological temperature. Meanwhile, PMM2 was sensitive to oxidative stress, and the cysteine pathogenic variants led to obvious aggregate formation and a higher cellular apoptosis ratio under oxidative stress. Molecular dynamic simulations indicated that the pathogenic variants changed the core domain of homomeric PMM2 and subunit binding free energy. Moreover, we tested the potential drug targeting PMM2-celastrol in cell level and explained the result by molecular docking simulation. In this study, we delineated the pathological mechanism of the cysteine substitution in PMM2, which addressed the vital role of cysteine in PMM2 and provided novel insights into prevention and treatment strategies for PMM2-CDG.

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βB2 W151R mutant is prone to degradation, aggregation and exposes the hydrophobic side chains in the fourth Greek Key motif

Cited by 17 publications

References 35 publications

Physiological and pathological functions of βB2-crystallins in multiple organs: a systematic review

Physiological and pathological functions of βB2-crystallins in multiple organs: a systematic review

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

Cysteine Pathogenic Variants of PMM2 Are Sensitive to Environmental Stress with Loss of Structural Stability

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