ATP13A1与SEC61结合促进底物特异性易位

IF 12.5 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Xiaoyan Yang, Yi Li, Chengxi Yang, Tingting Li, Zhiyu Fang, Zhigang Feng, Jun Liao, Yan Zou
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引用次数: 0

摘要

将蛋白质精确定位到其指定的细胞区室对于维持适当的细胞结构和功能至关重要。然而,对分泌蛋白和膜蛋白中高度可变的靶向序列进行解释和分类,对于在分泌途径中实现精确定位提出了重大挑战。在这项研究中,我们证明了非典型信号序列,其特点是高疏水性和/或缺乏特征电荷,被信号识别粒子识别并以相反的方向靶向内质网。这些定向错误的信号序列随后被P5A-ATPase ATP13A1错位,并传递给SEC61进行进一步的易位。使用低温电子显微镜,我们确定了人类ATP13A1的多种构象结构(3.40至3.87埃分辨率),揭示了其底物结合袋内通过极性相互作用参与信号序列的关键残基。总的来说,我们的发现阐明了一个全面的,底物特异性的易位途径,确保了蛋白质亚细胞定位的高效率和保真度。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

ATP13A1 engages SEC61 to facilitate substrate-specific translocation

ATP13A1 engages SEC61 to facilitate substrate-specific translocation
The accurate targeting of proteins to their designated cellular compartments is essential for maintaining proper cellular architecture and function. However, interpreting and sorting the highly variable targeting sequences in secreted and membrane proteins present a substantial challenge for achieving precise localization within the secretory pathway. In this study, we demonstrate that atypical signal sequences, characterized by high hydrophobicity and/or the absence of characteristic charges, are recognized by the signal recognition particle and targeted to the endoplasmic reticulum in a reverse orientation. These misoriented signal sequences are subsequently dislocated by the P5A-ATPase ATP13A1 and delivered to SEC61 for further translocation. Using cryo–electron microscopy, we determined the structures of human ATP13A1 in multiple conformations (3.40- to 3.87-angstrom resolution), revealing key residues within its substrate-binding pocket that engage signal sequences through polar interactions. Collectively, our findings elucidate a comprehensive, substrate-specific translocation pathway that ensures both high efficiency and fidelity in protein subcellular localization.
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来源期刊
Science Advances
Science Advances 综合性期刊-综合性期刊
CiteScore
21.40
自引率
1.50%
发文量
1937
审稿时长
29 weeks
期刊介绍: Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.
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