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

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

机构地区：[1]Eye Center of the Second Affiliated Hospital,Zhejiang University School of Medicine,88 Jiefang Road,Hangzhou 310009,China [2]Institute of Translational Medicine,Zhejiang University School of Medicine,268 Kaixuan Road,Hangzhou 310020,China. [3]State Key Laboratory of Membrane Biology,School of Life Sciences,Tsinghua University,Beijing 100084,China [4]The Children’s Hospital,Zhejiang University School of Medicine,National Clinical Research Center for Child Health,Hangzhou 310052,China [5]Zhejiang Province Key Laboratory of Quantum Technology and Device,Department of Physics,Zhejiang University,Zheda Road 38,Hangzhou 310027,China

出　　处：《Fundamental Research》2024年第2期394-400,共7页自然科学基础研究（英文版）

基　　金：supported by the National Natural Science Foundation of China(31872724,and 81900837);the Natural Science Foundation of Zhejiang Province(LR21H120001).

摘　　要：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 of αB-crystallin.In this work,based on the UNcle and SEC analysis,we found that celastrol induced𝛼αB-crystallin to form large oligomers.Large oligomer formation enhanced the chaperone activity of αB-crystallin and prevented aggregation of the cataract-causing mutant αA3-G91del.The interactions between𝛼αB-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 large αB-crystallin oligomers,which enhanced its chaperone activity,but also bound to the groove structure of its α-crystallin domain to maintain its structural stability.Celastrol might serve as a chemical and pharmacological chaperone for cataract treatment.

关 键 词：αB-crystallin CELASTROL INTERACTIONS Oligomeric state Chaperone activity Structural stability 

分 类 号：O63[理学—高分子化学]