Zhao Shuyue, Quan Shu, He Wei, Xu Linlin, Hu Haodong, Ma Zixuan, Ma Rujiang, Huang Fan, Shi Linqi
Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, P. R. China.
State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, Shanghai 200240, P. R. China.
J Am Chem Soc. 2025 May 7;147(18):15357-15368. doi: 10.1021/jacs.5c01133. Epub 2025 Apr 25.
Protein folding regulation is of great significance for maintaining protein structures and biological functions. This fundamental process is assisted by molecular chaperones, which act in inhibiting undesired protein aggregation and facilitating misfolded protein refolding. Inspired by the unique structure and ingenious mechanisms of natural Spy chaperones, we innovate a nanochaperone-guided protein folding strategy by rationally designed nanochaperones (nChaps) with customizable surface structures and properties. In this strategy, the nChaps with tunable charged surfaces can first rapidly capture different client proteins through long-range electrostatic attraction, similar to Spy. Subsequently, the captured proteins can be dynamically bound into the Spy-mimetic hydrophobic microdomains via short-range hydrophobic interactions. As a result, the client proteins are sequestered and stabilized in the chaperone-mimicking confined spaces on the surface of nChaps, thereby facilitating dynamic regulation of protein folding through an electrostatic-hydrophobic synergy mechanism. Moreover, benefiting from the adjustable charge and multiple hydrophobic microdomains, this biomimetic nChap potentiates protein stability at harsh temperatures and long-term storage, which is hardly achieved by natural Spy. Additionally, this strategy is applicable to 9 different proteins with varying isoelectric points and molecular weights, showing superior generality than Spy. Therefore, this work provides new perspectives in developing an advanced strategy for enhanced protein folding regulation.
蛋白质折叠调控对于维持蛋白质结构和生物学功能具有重要意义。这一基本过程由分子伴侣协助，分子伴侣可抑制不期望的蛋白质聚集并促进错误折叠蛋白质的重新折叠。受天然Spy分子伴侣独特结构和巧妙机制的启发，我们通过合理设计具有可定制表面结构和性质的纳米分子伴侣（nChaps），创新了一种纳米分子伴侣引导的蛋白质折叠策略。在该策略中，具有可调电荷表面的nChaps首先可通过长程静电吸引快速捕获不同的目标蛋白，类似于Spy。随后，捕获的蛋白质可通过短程疏水相互作用动态结合到模拟Spy的疏水微域中。结果，目标蛋白被隔离并稳定在nChaps表面模拟分子伴侣的受限空间中，从而通过静电 - 疏水协同机制促进蛋白质折叠的动态调控。此外，受益于可调节的电荷和多个疏水微域，这种仿生nChap在苛刻温度和长期储存条件下增强了蛋白质稳定性，这是天然Spy难以实现的。此外，该策略适用于9种不同等电点和分子量的蛋白质，显示出比Spy更高的通用性。因此，这项工作为开发增强蛋白质折叠调控的先进策略提供了新的视角。
