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科学家解析溶酶体卵泡蛋白复合物结构
作者:小柯机器人 发布时间:2019/11/1 17:25:24

美国加州大学伯克利分校James H. Hurley和Roberto Zoncu研究组,合作解析了溶酶体卵泡蛋白复合物激活Rag GTPase检查点的结构机制。 10月31日出版的《科学》在线发表了这项成果。

为了确定肿瘤抑制因子(FLCN)的溶酶体功能,研究人员重构了溶酶体FLCN复合物(LFC),其中包含FLCN、以及FLCN相互作用蛋白2(FNIP2)、RagAGDP:RagCGTP GTPases;在饥饿状态下,这些蛋白存在于它们的溶酶体锚定复合物Ragulator中,研究人员并解析了这个复合物3.6Å的冷冻电镜结构。 FLCN的RagC-GAP活性在LFC中受到抑制,因为从RagC核苷酸置换了FLCN中催化所需的精氨酸。

LCN的解体和FLCN的RagC-GAP活性的释放揭示了mTORC1依赖性的溶酶体生物发生过程,这提示LFC作为mTORC1信号转导的检查点。

据介绍,肿瘤抑制因子通过其鸟嘌呤三磷酸酶(GTPase)激活蛋白(GAP)调控GTPase RagC的活性,能营养依赖性的激活其靶标雷帕霉素复合物1(mTORC1)蛋白激酶活性。伴随饥饿引起的mTORC1失活,FLCN从胞质重新回到到溶酶体。

附:英文原文

Title: Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex

Author: Rosalie E. Lawrence, Simon A. Fromm, Yangxue Fu, Adam L. Yokom, Do Jin Kim, Ashley M. Thelen, Lindsey N. Young, Chun-Yan Lim, Avi J. Samelson, James H. Hurley, Roberto Zoncu

Issue&Volume: 2019/10/31

Abstract: AbstractThe tumor suppressor folliculin (FLCN) enables nutrient-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) protein kinase via its guanosine triphosphatase (GTPase) Activating Protein (GAP) activity toward the GTPase RagC. Concomitant with mTORC1 inactivation by starvation, FLCN relocalizes from the cytosol to lysosomes. To determine the lysosomal function of FLCN, we reconstituted the lysosomal FLCN complex (LFC) containing FLCN, its partner FLCN-interacting protein 2 (FNIP2), the RagAGDP:RagCGTP GTPases as they exist in the starved state with their lysosomal anchor Ragulator complex, and determined its cryo-EM structure to 3.6 . The RagC-GAP activity of FLCN was inhibited within LFC, due to displacement of a catalytically required Arginine in FLCN from the RagC nucleotide. Disassembly of the LFC and release of the RagC-GAP activity of FLCN enabled mTORC1-dependent regulation of the master regulator of lysosomal biogenesis, transcription factor E3, implicating the LFC as a checkpoint in mTORC1 signaling.

DOI: 10.1126/science.aax0364

Source: https://science.sciencemag.org/content/early/2019/10/30/science.aax0364

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037