丹麦技术大学教授Buell, Alexander K.团队报道了淀粉样蛋白原纤维生长的机制的Φ值分析。相关研究成果发表在2025年1月16日出版的《自然—化学》。

淀粉样纤维是高度稳定的错误折叠的蛋白质组装体，在几种神经退行性疾病和全身性疾病中起着重要作用。尽管淀粉样蛋白状态的结构信息现在很丰富，但关于错误折叠过程的机制细节仍然难以捉摸。

受蛋白质折叠Φ值分析的启发，研究人员结合实验和分子模拟来解决氨基酸接触问题，并确定PI3K-SH3淀粉样原纤维伸长的过渡态集合结构——限速步骤。该集合通过Tanfordβ分析进行了实验验证，并通过自由能计算进行了计算验证。

尽管蛋白质折叠是在漏斗形的景观上进行的，但在这里发现，错误折叠反应的能量景观由一个大的“高尔夫球场”区域组成，该区域由单一的能量屏障和过渡态定义，进入一个急剧漏斗形的区域。因此，错误折叠是由罕见的、成功的单体-原纤维末端碰撞发生的，其间穿插着无数不成功的结合尝试。

综上所述，这些见解为蛋白质错误折叠反应提供了定量和高度解析的描述。

附：英文原文

Title: The mechanism of amyloid fibril growth from Φ-value analysis

Author: Larsen, Jacob Aunstrup, Barclay, Abigail, Vettore, Nicola, Klausen, Louise K., Mangels, Lena N., Coden, Alberto, Schmit, Jeremy D., Lindorff-Larsen, Kresten, Buell, Alexander K.

Issue&Volume: 2025-01-16

Abstract: Amyloid fibrils are highly stable misfolded protein assemblies that play an important role in several neurodegenerative and systemic diseases. Although structural information of the amyloid state is now abundant, mechanistic details about the misfolding process remain elusive. Inspired by the Φ-value analysis of protein folding, we combined experiments and molecular simulations to resolve amino-acid contacts and determine the structure of the transition-state ensemble—the rate-limiting step—for fibril elongation of PI3K-SH3 amyloid fibrils. The ensemble was validated experimentally by Tanford β analysis and computationally by free energy calculations. Although protein folding proceeds on funnel-shaped landscapes, here we find that the energy landscape for the misfolding reaction consists of a large ‘golf course’ region, defined by a single energy barrier and transition state, accessing a sharply funnelled region. Thus, misfolding occurs by rare, successful monomer–fibril end collisions interspersed by numerous unsuccessful binding attempts. Taken together, these insights provide a quantitative and highly resolved description of a protein misfolding reaction.

DOI: 10.1038/s41557-024-01712-9

Source: https://www.nature.com/articles/s41557-024-01712-9