晶状体蛋白识别互作与白内障的研究进展

Research Progress of Molecular Recognition and Interaction of Crystallins Linking Cataract

白内障是全球致盲率最高的眼科疾病,发病组织为晶状体.晶状体内纤维细胞含有高浓度的晶状体蛋白,晶状体蛋白家族分α-,β-和γ-3大亚家族.α-晶状体蛋白具有小分子伴侣功能,可识别错误折叠蛋白质,维持晶状体内蛋白质稳态;β-/γ-晶状体蛋白通过分子内或分子间相互作用,主要发挥结构蛋白功能.晶状体蛋白在晶状体纤维细胞内呈瞬时有序排列,精准分子识别及动态相互作用在维持晶状体透明度中发挥关键作用.晶状体内蛋白质稳态失衡是白内障的主要致病因素.晶状体蛋白半衰期长,且翻译合成后不再更新,广泛受pH值、金属离子、辐射损伤和蛋白质翻译后修饰等细胞内外环境因素和化学因素的干扰,影响晶状体蛋白间的分子识别和相互作用,诱发白内障.理清化学调控的晶状体蛋白分子识别及互作调控,有助于阐明白内障发病机理,并发掘防治白内障的创新策略.本文基于晶状体蛋白识别互作与白内障研究进展,综合评述了晶状体蛋白的分子识别、相互作用方式、调控因素及研究技术创新,并探讨了晶状体蛋白识别互作调控网络在白内障药物研发的应用价值与挑战.

Cataract formation is the leading cause of blindness across the globe.The eye lens is the onset site of cataract.The eye lens is densely packed with crystallins at a high concentration.Crystallins are categorized into 3 distinct families:α-,β-,andγ-CRYs.Theα-CRYs are known to function as a small molecule chaperone,recognizing misfolded proteins and maintaining protein homeostasis in the lens.While theβ-/γ-CRYs serve a key structural role in lens formation through intramolecular and intermolecular interactions.Crystallins are arranged in transiently short-range order within the lens fibers.In addition,the molecular recognition and dynamic protein interactions that are medicated by crystallins serve a critical role in maintaining the transparency of the eye lens.Protein homeostasis disorder in eye lens is the main pathogenic factors causing cataract.The crystallins have a long half-life and no longer renewed after protein synthesis.Therefore,the crystallins are highly susceptible to both the extracellular and intracellular factors,such as pH,metal ions,radiation damage and post-translational modifications.These factors disrupt molecular recognition of the crystallins or alter protein-protein interactions,resulting in cataract formation.Identifying the chemical regulatory principles of molecular recognition and protein interactions of the crystallins can help elucidate the molecular mechanisms that maintain or disrupt lens transparency,along with developing innovative treatment strategies for cataract.In this review,based on recent progress in crystallins and cataracts,we comprehensively summarized the way of molecular recognition and protein interaction in the crystallins,as well as the regulatory factors.Recent technological innovations that were enabling us to characterize interactions between the crystallins were further discussed.In addition,we investigated the application values and challenges of protein-protein interaction networks that were dominated by the crystallins in the anti-cataract drug development.