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

Jingjie Xu; Huaxia Wang; Ailing Wang; Jia Xu; Chenxi Fu; Zhekun Jia; Ke Yao; Xiangjun Chen

doi:10.1016/j.bbadis.2020.166018

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

Biochim Biophys Acta Mol Basis Dis. 2021 Feb 1;1867(2):166018. doi: 10.1016/j.bbadis.2020.166018. Epub 2020 Nov 25.

Authors

Jingjie Xu¹, Huaxia Wang², Ailing Wang², Jia Xu¹, Chenxi Fu¹, Zhekun Jia¹, Ke Yao³, Xiangjun Chen⁴

Affiliations

¹ Eye Center of the Second Affiliated Hospital, Medical College of Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China.
² Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310020, China.
³ Eye Center of the Second Affiliated Hospital, Medical College of Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China. Electronic address: [email protected].
⁴ Eye Center of the Second Affiliated Hospital, Medical College of Zhejiang University, 88 Jiefang Road, Hangzhou 310009, China; Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310020, China. Electronic address: [email protected].

PMID: 33246011
DOI: 10.1016/j.bbadis.2020.166018

Abstract

Studies have established that congenital cataract is the major cause of blindness in children across the globe. The β-crystallin protein family is the richest and most soluble structural protein in the lens. Their solubility and stability are essential in maintaining lens transparency. In this study, we identified a novel βB2 mutation W151R in a rare progressive cortical congenital cataract family and explored its pathogenesis using purified protein and mutant related cataract-cell models. Due to its low solubility and poor structural stability, the βB2 W151R mutation was prone to aggregation. Moreover, the W151R mutation enhanced the exposure of the hydrophobic side chains in the fourth Greek Key motif, which were readily degraded by trypsin. However, upon the administration of lanosterol, the negative effect of the W151R mutation was reversed. Therefore, lanosterol is a potential therapeutic option for cataracts.

Keywords: Cataract-causing mutation; Protein aggregation; Protein degradation; βB2-crystallin.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Cataract / congenital*
Cataract / drug therapy
Cataract / genetics
Cataract / pathology
Child, Preschool
DNA Mutational Analysis
Female
HEK293 Cells
HeLa Cells
Humans
Hydrophobic and Hydrophilic Interactions / drug effects
Lanosterol / pharmacology
Lanosterol / therapeutic use*
Lens, Crystalline / drug effects
Lens, Crystalline / pathology*
Male
Molecular Dynamics Simulation
Mutagenesis, Site-Directed
Mutation
Pedigree
Protein Aggregation, Pathological / congenital
Protein Aggregation, Pathological / drug therapy
Protein Aggregation, Pathological / genetics*
Protein Conformation, beta-Strand / drug effects
Protein Conformation, beta-Strand / genetics
Proteolysis / drug effects
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Recombinant Proteins / isolation & purification
Recombinant Proteins / metabolism
Trypsin / metabolism
beta-Crystallin B Chain / chemistry
beta-Crystallin B Chain / genetics*
beta-Crystallin B Chain / isolation & purification
beta-Crystallin B Chain / metabolism

Substances

Recombinant Proteins
beta-Crystallin B Chain
beta-crystallin B2
Lanosterol
Trypsin

Supplementary concepts

Cataract, Progressive Polymorphic Cortical