首页|Celastrol regulates the oligomeric state and chaperone activity of αB-crystallin linked with protein homeostasis in the lens

Celastrol regulates the oligomeric state and chaperone activity of αB-crystallin linked with protein homeostasis in the lens

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Protein misfolding and aggregation are crucial pathogenic factors for cataracts,which are the leading cause of visual impairment worldwide.α-crystallin,as a small molecular chaperone,is involved in preventing protein misfolding and maintaining lens transparency.The chaperone activity of α-crystallin depends on its oligomeric state.Our previous work identified a natural compound,celastrol,which could regulate the oligomeric state ofαB-crystallin.In this work,based on the UNcle and SEC analysis,we found that celastrol induced αB-crystallin to form large oligomers.Large oligomer formation enhanced the chaperone activity of αB-crystallin and prevented aggregation of the cataract-causing mutant βA3-G91del.The interactions between αB-crystallin and celastrol were detected by the FRET(Fluorescence Resonance Energy Transfer)technique,and verified by molecular docking.At least 9 binding patterns were recognized,and some binding sites covered the groove structure of αB-crystallin.Interestingly,αB-R120G,a cataract-causing mutation located at the groove structure,and celastrol can decrease the aggregates of αB-R120G.Overall,our results suggested celastrol not only promoted the formation of largeαB-crystallin oligomers,which enhanced its chaperone activity,but also bound to the groove structure of itsα-crystallin domain to maintain its structural stability.Celastrol might serve as a chemical and pharmacological chaperone for cataract treatment.

αB-crystallinCelastrolInteractionsOligomeric stateChaperone activityStructural stability

Huaxia Wang、Qing Tian、Ying Zhang、Yibo Xi、Lidan Hu、Ke Yao、Jingyuan Li、Xiangjun Chen

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Eye Center of the Second Affiliated Hospital,Zhejiang University School of Medicine,88 Jiefang Road,Hangzhou 310009,China

Institute of Translational Medicine,Zhejiang University School of Medicine,268 Kaixuan Road,Hangzhou 310020,China

State Key Laboratory of Membrane Biology,School of Life Sciences,Tsinghua University,Beijing 100084,China

The Children's Hospital,Zhejiang University School of Medicine,National Clinical Research Center for Child Health,Hangzhou 310052,China

Zhejiang Province Key Laboratory of Quantum Technology and Device,Department of Physics,Zhejiang University,Zheda Road 38,Hangzhou 310027,China

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国家自然科学基金国家自然科学基金浙江省自然科学基金

3187272481900837LR21H120001

2024

10.1016/j.fmre.2022.05.012

自然科学基础研究(英文)

自然科学基础研究(英文)

CSTPCD
ISSN：
年,卷(期)：2024.(2)
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