Ikenoue Tatsuya, So Masatomo, Terasaka Naohiro, Huang Wei-En, Kawata Yasushi, Miyanoiri Yohei, Kamagata Kiyoto, Suga Hiroaki
Department of Chemistry, The University of Tokyo, Tokyo 113-0033, Japan.
Institute for Protein Research, The University of Osaka, Osaka 565-0871, Japan.
J Am Chem Soc. 2025 Jul 9;147(27):24113-24126. doi: 10.1021/jacs.5c08019. Epub 2025 Jun 25.
Liquid-liquid phase separation (LLPS) of proteins can form membraneless organelles in the cell and can lead to pathological aggregation associated with neurodegenerative diseases. However, progress in controlling LLPS has been limited, and there has been no emergence of engineered molecules to induce and modulate LLPS of targeted proteins. Here, we report peptides that efficiently induce the LLPS of α-synuclein (αSyn), a protein involved in Parkinson's disease, discovered by the RaPID (random nonstandard peptides integrated discovery) system. These peptides primarily interact with the C-terminal region of αSyn, leading to the formation of an interaction network with αSyn and resulting in efficient droplet formation. Our study demonstrates the capacity of target-specific peptides to control LLPS and the subsequent liquid-solid phase transition (LSPT). Our novel LLPS-inducing and LSPT-modulating peptides may serve as a promising tool for fundamental investigations of LLPS and potentially for therapeutic intervention in amyloid diseases.
蛋白质的液-液相分离（LLPS）可在细胞中形成无膜细胞器，并可导致与神经退行性疾病相关的病理性聚集。然而，在控制LLPS方面进展有限，尚未出现可诱导和调节靶向蛋白质LLPS的工程分子。在此，我们报告了通过RaPID（随机非标准肽整合发现）系统发现的、能有效诱导参与帕金森病的蛋白质α-突触核蛋白（αSyn）发生LLPS的肽。这些肽主要与αSyn的C末端区域相互作用，导致与αSyn形成相互作用网络并有效形成液滴。我们的研究证明了靶向特异性肽控制LLPS及随后液-固相变（LSPT）的能力。我们新型的LLPS诱导和LSPT调节肽可能成为LLPS基础研究以及潜在用于淀粉样疾病治疗干预的有前景的工具。
