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过氧化物酶体泛素连接酶复合物形成了逆向转运通道
2022-06-30 19:52

美国哈佛医学院Tom A. Rapoport和Peiqiang Feng共同合作,近期取得重要工作进展。他们研究发现过氧化物酶体泛素连接酶复合物形成了逆向转运通道。相关论文2022年6月29日在线发表于《自然》杂志上。

研究人员报告了连接酶复合物的低温电子显微镜结构,结合生化和体内实验揭示了它作为过氧化物酶体输入受体的逆向易位通道的功能。该复合物的每个亚基贡献了五个跨膜片段,这些片段共同组装成一个开放通道。三个环指结构域形成一个胞质塔,环指2(RF2)位于通道孔上方。研究人员提出,将回收受体的N末端从过氧化物酶体腔插入到孔中,并通过RF2进行单泛素化,从而能够提取到细胞质中。如果再循环受到损害,受体会在RF10和RF12的协同作用下被多泛素化并降解。这种多泛素化途径还维持其他过氧化物酶体输入因子的稳态。

他们的研究结果阐明了过氧化物酶体蛋白导入过程中的关键步骤,并揭示了连接酶复合物突变导致人类疾病的原因。

据介绍,过氧化物酶体是一种普遍存在的细胞器,可容纳各种代谢反应,对人类健康至关重要。Luminal过氧化物酶体蛋白通过移动受体从细胞质中导入,然后通过一个鲜为人知的过程循环到细胞质中。再循环需要通过膜嵌入的泛素连接酶复合物对受体进行修饰,该复合物包含三个环指结构域蛋白(Pex2、Pex10和Pex12)。

附:英文原文

Title: A peroxisomal ubiquitin ligase complex forms a retrotranslocation channel

Author: Feng, Peiqiang, Wu, Xudong, Erramilli, Satchal K., Paulo, Joao A., Knejski, Pawel, Gygi, Steven P., Kossiakoff, Anthony A., Rapoport, Tom A.

Issue&Volume: 2022-06-29

Abstract: Peroxisomes are ubiquitous organelles that house various metabolic reactions and are essential for human health1,2,3,4. Luminal peroxisomal proteins are imported from the cytosol by mobile receptors, which then recycle back to the cytosol by a poorly understood process1,2,3,4. Recycling requires receptor modification by a membrane-embedded ubiquitin ligase complex comprising three RING finger domain-containing proteins (Pex2, Pex10 and Pex12)5,6. Here we report a cryo-electron microscopy structure of the ligase complex, which together with biochemical and in vivo experiments reveals its function as a retrotranslocation channel for peroxisomal import receptors. Each subunit of the complex contributes five transmembrane segments that co-assemble into an open channel. The three ring finger domains form a cytosolic tower, with ring finger 2 (RF2) positioned above the channel pore. We propose that the N terminus of a recycling receptor is inserted from the peroxisomal lumen into the pore and monoubiquitylated by RF2 to enable extraction into the cytosol. If recycling is compromised, receptors are polyubiquitylated by the concerted action of RF10 and RF12 and degraded. This polyubiquitylation pathway also maintains the homeostasis of other peroxisomal import factors. Our results clarify a crucial step during peroxisomal protein import and reveal why mutations in the ligase complex cause human disease.

DOI: 10.1038/s41586-022-04903-x

Source: https://www.nature.com/articles/s41586-022-04903-x

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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