Qi Xingmei, Wang Yu, Yu Hairui, Liu Ruifang, Leppert Axel, Zheng Zihan, Zhong Xueying, Jin Zhen, Wang Han, Li Xiaoli, Wang Xiuzhe, Landreh Michael, A Morozova-Roche Ludmilla, Johansson Jan, Xiong Sidong, Iashchishyn Igor, Chen Gefei
The Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, 215123, China.
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, 14157, Sweden.
Small. 2023 Nov;19(46):e2304031. doi: 10.1002/smll.202304031. Epub 2023 Jul 16.
Amyloid fibrils-nanoscale fibrillar aggregates with high levels of order-are pathogenic in some today incurable human diseases; however, there are also many physiologically functioning amyloids in nature. The process of amyloid formation is typically nucleation-elongation-dependent, as exemplified by the pathogenic amyloid-β peptide (Aβ) that is associated with Alzheimer's disease. Spider silk, one of the toughest biomaterials, shares characteristics with amyloid. In this study, it is shown that forming amyloid-like nanofibrils is an inherent property preserved by various spider silk proteins (spidroins). Both spidroins and Aβ capped by spidroin N- and C-terminal domains, can assemble into macroscopic spider silk-like fibers that consist of straight nanofibrils parallel to the fiber axis as observed in native spider silk. While Aβ forms amyloid nanofibrils through a nucleation-dependent pathway and exhibits strong cytotoxicity and seeding effects, spidroins spontaneously and rapidly form amyloid-like nanofibrils via a non-nucleation-dependent polymerization pathway that involves lateral packing of fibrils. Spidroin nanofibrils share amyloid-like properties but lack strong cytotoxicity and the ability to self-seed or cross-seed human amyloidogenic peptides. These results suggest that spidroins´ unique primary structures have evolved to allow functional properties of amyloid, and at the same time direct their fibrillization pathways to avoid formation of cytotoxic intermediates.
淀粉样纤维——具有高度有序性的纳米级纤维状聚集体——在一些目前无法治愈的人类疾病中具有致病性；然而，自然界中也存在许多具有生理功能的淀粉样蛋白。淀粉样蛋白的形成过程通常依赖于成核-延伸，以与阿尔茨海默病相关的致病性淀粉样β肽（Aβ）为例。蜘蛛丝是最坚韧的生物材料之一，与淀粉样蛋白具有共同特征。在本研究中，结果表明形成淀粉样样纳米纤维是各种蜘蛛丝蛋白（蛛丝蛋白）保留的固有特性。由蛛丝蛋白N端和C端结构域封端的蛛丝蛋白和Aβ都可以组装成宏观的蜘蛛丝样纤维，这些纤维由与天然蜘蛛丝中观察到的平行于纤维轴的直纳米纤维组成。虽然Aβ通过依赖成核的途径形成淀粉样纳米纤维，并表现出强烈的细胞毒性和种子效应，但蛛丝蛋白通过涉及纤维横向堆积的非依赖成核的聚合途径自发且快速地形成淀粉样样纳米纤维。蛛丝蛋白纳米纤维具有类似淀粉样蛋白的特性，但缺乏强烈的细胞毒性以及自我种子化或交叉种子化人类淀粉样生成肽的能力。这些结果表明，蛛丝蛋白独特的一级结构已经进化，以允许具有淀粉样蛋白的功能特性，同时引导它们的纤维化途径，以避免形成细胞毒性中间体。
