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头条:SEA复合物的冷冻电镜结构

时间:2022-11-06 08:57:13       来源:今日科学


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瑞士日内瓦大学Robbie Loewith团队近期取得重要工作进展,他们研究揭示了SEA复合物的冷冻电镜结构。这一研究成果2022年10月26日在线发表于《自然》杂志上。

研究人员解析了天然八亚基SEAC的冷冻电镜结构。SEAC有一个模块化的结构,其中一个与SEACAT相对应的类似COPII的笼子结合了两个灵活的翅膀,这与SEACIT相对应。翅膀结构通过Sea3与核心相连,Sea3是两个模块的组成部分。GATOR1的GAP机制在SEACIT中是保守的,GAP活性在体外不受SEACAT的影响。在体内,翅膀是招募SEAC到液泡的关键,主要是通过EGO复合物。结果表明,SEACAT不是SEACIT的直接抑制剂,而是作为TORC1调控因子结合的支架。

据介绍,SEA复合体(SEAC)是一种生长调节剂,它作为GTPase激活蛋白(GAP)作用于Gtr1, Gtr1是一种Rag GTPase,它将营养状态传递到酵母中雷帕霉素复合体1的靶蛋白(TORC1)。在功能上,SEAC被分为两个亚复合物:具有GAP活性并抑制TORC1的SEACIT和调控SEACIT的SEACAT。这个系统在哺乳动物中是保守的:GATOR复合体,由GATOR1(SEACIT)和GATOR2(SEACAT)组成,向mTORC1传递氨基酸和葡萄糖信号。尽管SEAC/GATOR很重要,但它的结构和对其功能的分子理解仍然缺乏。

附:英文原文

Title: Cryo-EM structure of the SEA complex

Author: Tafur, Lucas, Hinterndorfer, Kerstin, Gabus, Caroline, Lamanna, Chiara, Bergmann, Ariane, Sadian, Yashar, Hamdi, Farzad, Kyrilis, Fotis L., Kastritis, Panagiotis L., Loewith, Robbie

Issue&Volume: 2022-10-26

Abstract: The SEA complex (SEAC) is a growth regulator that acts as a GTPase-activating protein (GAP) towards Gtr1, a Rag GTPase that relays nutrient status to the Target of Rapamycin Complex 1 (TORC1) in yeast1. Functionally, the SEAC has been divided into two subcomplexes: SEACIT, which has GAP activity and inhibits TORC1, and SEACAT, which regulates SEACIT2. This system is conserved in mammals: the GATOR complex, consisting of GATOR1 (SEACIT) and GATOR2 (SEACAT), transmits amino acid3 and glucose4 signals to mTORC1. Despite its importance, the structure of SEAC/GATOR, and thus molecular understanding of its function, is lacking. Here, we solve the cryo-EM structure of the native eight-subunit SEAC. The SEAC has a modular structure in which a COPII-like cage corresponding to SEACAT binds two flexible wings, which correspond to SEACIT. The wings are tethered to the core via Sea3, which forms part of both modules. The GAP mechanism of GATOR1 is conserved in SEACIT, and GAP activity is unaffected by SEACAT in vitro. In vivo, the wings are essential for recruitment of the SEAC to the vacuole, primarily via the EGO complex. Our results indicate that rather than being a direct inhibitor of SEACIT, SEACAT acts as a scaffold for the binding of TORC1 regulators.

DOI: 10.1038/s41586-022-05370-0

Source: https://www.nature.com/articles/s41586-022-05370-0

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标签: 结果表明 哺乳动物 组成部分

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