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The Aggregation of αB-Crystallin under Crowding Conditions Is Prevented by αA-Crystallin: Implications for α-Crystallin Stability and Lens Transparency.
Journal of Molecular Biology ( IF 5.6 ) Pub Date : 2020-08-19 , DOI: 10.1016/j.jmb.2020.08.011
Aidan B Grosas 1 , Agata Rekas 2 , Jitendra P Mata 3 , David C Thorn 1 , John A Carver 1
Affiliation  

One of the most crowded biological environments is the eye lens which contains a high concentration of crystallin proteins. The molecular chaperones αB-crystallin (αBc) with its lens partner αA-crystallin (αAc) prevent deleterious crystallin aggregation and cataract formation. However, some forms of cataract are associated with structural alteration and dysfunction of αBc. While many studies have investigated the structure and function of αBc under dilute in vitro conditions, the effect of crowding on these aspects is not well understood despite its in vivo relevance. The structure and chaperone ability of αBc under conditions that mimic the crowded lens environment were investigated using the polysaccharide Ficoll 400 and bovine γ-crystallin as crowding agents and a variety of biophysical methods, principally contrast variation small-angle neutron scattering. Under crowding conditions, αBc unfolds, increases its size/oligomeric state, decreases its thermal stability and chaperone ability, and forms kinetically distinct amorphous and fibrillar aggregates. However, the presence of αAc stabilizes αBc against aggregation. These observations provide a rationale, at the molecular level, for the aggregation of αBc in the crowded lens, a process that exhibits structural and functional similarities to the aggregation of cataract-associated αBc mutants R120G and D109A under dilute conditions. Strategies that maintain or restore αBc stability, as αAc does, may provide therapeutic avenues for the treatment of cataract.



中文翻译:

αA-Crystallin可防止在拥挤条件下αB-Crystallin的聚集:对α-Crystallin稳定性和晶状体透明度的影响。

最拥挤的生物环境之一是眼晶状体,其中含有高浓度的晶状体蛋白。分子伴侣αB-晶状蛋白(αBc)及其晶状体伴侣αA-晶状蛋白(αAc)可防止有害的晶状蛋白聚集和白内障形成。但是,某些形式的白内障与αBc的结构改变和功能障碍有关。尽管许多研究已经在体外稀释条件下研究了αBc的结构和功能,但是尽管它们在体内,但对这些方面的拥挤效果尚不甚了解关联。以多糖Ficoll 400和牛γ-晶状蛋白为拥挤剂并采用多种生物物理方法,主要是对比度变化小角度中子散射,研究了模拟拥挤透镜环境下αBc的结构和分子伴侣能力。在拥挤条件下,αBc会展开,增加其尺寸/低聚状态,降低其热稳定性和分子伴侣能力,并形成动力学上独特的无定形和原纤维聚集体。但是,αAc的存在可以稳定αBc防止聚集。这些观察结果在分子水平上为拥挤晶状体中αBc的聚集提供了理论依据,该过程与稀疏条件下与白内障相关的αBc突变体R120G和D109A的聚集表现出结构和功能的相似性。

更新日期:2020-09-30
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