近日，英国弗朗西斯克里克研究所的Fani Panagaki及其研究团队取得一项新进展。经过不懈努力，他们发现结构各向异性导致蛋白质在核孔中的机械定向输运。相关研究成果已于2024年5月13日在国际知名学术期刊《自然—物理学》上发表。
该研究团队发现在核定位序列附近具有局部软区的蛋白质表现出更高的核输入率，并且这种机械选择性在敲减核孔蛋白153(核孔复合体中的关键蛋白)时特别容易受损。这使研究人员能够设计一种短的、易于表达的、化学惰性的非结构化肽标记，以加速硬蛋白货物的核输入速率。
研究人员还发现，表达肽标记的心肌素相关转录因子的U2OS骨肉瘤细胞以更高的速率将这种机械敏感蛋白导入细胞核，并表现出更快的运动性。这一发现表明，蛋白质中的局部非结构化区域能够降低蛋白质易位的自由能垒，可能为核机械转导提供了一种新的控制机制。
据悉，核孔复合体通过一系列紧密协调的生化反应来调控核胞质的转运过程。在这一过程中，转运货物的物理化学特性正在成为影响穿梭动力学的关键因素。除了分子量和表面暴露的氨基酸的影响外，蛋白质货物的核转位动力学还受到其纳米力学性质的显著影响。然而，关于核孔复合体如何实现机械选择性的具体机制，目前尚不十分明确。
附：英文原文
Title: Structural anisotropy results in mechano-directional transport of proteins across nuclear pores
Author: Panagaki, Fani, Tapia-Rojo, Rafael, Zhu, Tong, Milmoe, Natalie, Paracuellos, Patricia, Board, Stephanie, Mora, Marc, Walker, Jane, Rostkova, Elena, Stannard, Andrew, Infante, Elvira, Garcia-Manyes, Sergi
Issue&Volume: 2024-05-13
Abstract: The nuclear pore complex regulates nucleocytoplasmic transport by means of a tightly synchronized suite of biochemical reactions. The physicochemical properties of the translocating cargos are emerging as master regulators of their shuttling dynamics. As well as being affected by molecular weight and surface-exposed amino acids, the kinetics of the nuclear translocation of protein cargos also depend on their nanomechanical properties, yet the mechanisms underpinning the mechanoselectivity of the nuclear pore complex are unclear. Here we show that proteins with locally soft regions in the vicinity of the nuclear-localization sequence exhibit higher nuclear-import rates, and that such mechanoselectivity is specifically impaired upon knocking down nucleoporin 153, a key protein in the nuclear pore complex. This allows us to design a short, easy-to-express and chemically inert unstructured peptide tag that accelerates the nuclear-import rate of stiff protein cargos. We also show that U2OS osteosarcoma cells expressing the peptide-tagged myocardin-related transcription factor import this mechanosensitive protein to the nucleus at higher rates and display faster motility. Locally unstructured regions lower the free-energy barrier of protein translocation and might offer a control mechanism for nuclear mechanotransduction.
DOI: 10.1038/s41567-024-02438-8
Source: https://www.nature.com/articles/s41567-024-02438-8