Bari Khandekar Jishan, Sharma Shrikant
Center for Interdisciplinary Sciences, Tata Institute of Fundamental Research, Gopanpally, Hyderabad 500107, India.
Department of Chemical Sciences, Indian Institute of Science Education and Research, Berhampur, Odisha 760010, India.
J Phys Chem B. 2020 Dec 10;124(49):11041-11054. doi: 10.1021/acs.jpcb.0c07449. Epub 2020 Oct 14.
Lens crystallins are subject to various types of damage during their lifetime which triggers protein misfolding and aggregation, ultimately causing cataracts. There are several models for crystallin aggregation, but a comprehensive picture of the mechanism of cataract is still underway. The complex biomolecular interactions underlying crystallin aggregation have motivated major efforts to resolve the structural details and mechanism of aggregation using multiple biophysical techniques at different resolutions. Together, experimental and computational approaches identify and characterize both amyloidogenic and amorphous aggregates leading to an improved understanding of crystallin aggregation. A rigorous characterization of the aggregation-prone intermediates is crucial in cataract-mediated drug discovery. This Perspective summarizes recent biophysical studies on lens crystallin aggregation. We evaluate the outstanding challenges, future outlook, and rewards in this fertile field of research. With lessons learned from protein folding and multiple pathways of aggregation, we highlight the differences in the overall mechanisms of age-related and congenital cataracts. We expect that a correlation between the existing and developing biophysical techniques would provide a platform to study amyloid architecture in the eye lens and reduce the existing gaps in our understanding of crystallin biophysics.
晶状体蛋白在其生命周期中会受到各种类型的损伤，这会引发蛋白质错误折叠和聚集，最终导致白内障。目前有几种晶状体蛋白聚集模型，但白内障形成机制的全貌仍在研究之中。晶状体蛋白聚集背后复杂的生物分子相互作用促使人们做出了重大努力，运用多种不同分辨率的生物物理技术来解析聚集的结构细节和机制。实验方法和计算方法共同确定并表征了淀粉样聚集物和无定形聚集物，从而增进了对晶状体蛋白聚集的理解。对易于聚集的中间体进行严格表征对于白内障介导的药物发现至关重要。本综述总结了近期关于晶状体蛋白聚集的生物物理研究。我们评估了这一活跃研究领域中存在的突出挑战、未来前景和回报。借鉴蛋白质折叠和多种聚集途径的经验教训，我们强调了年龄相关性白内障和先天性白内障整体机制的差异。我们期望现有和正在发展的生物物理技术之间的关联能够提供一个平台，用于研究晶状体中的淀粉样结构，并缩小我们在晶状体蛋白生物物理学理解方面存在的差距。
