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首页> 外文期刊>Biochemistry >Structural Analysis and Functional Implications of the Negative mTORC1 Regulator REDD1,
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Structural Analysis and Functional Implications of the Negative mTORC1 Regulator REDD1,

机译：mTORC1负调节剂REDD1的结构分析和功能含义，

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REDD1 is a conserved stress-response protein that regulates mTORC1, a critical regulator ofncell growth and proliferation that is implicated in cancer. REDD1 is induced by hypoxia, and REDD1noverexpression is sufficient to inhibit mTORC1. mTORC1 is regulated by the small GTPase Rheb, which innturn is regulated by the GTPase-activating protein complex, TSC1/TSC2. REDD1 induced-mTORC1ninhibition requires the TSC1/TSC2 complex, and REDD1 has been proposed to act by directly binding tonand sequestering 14-3-3 proteins away from TSC2 leading to TSC2-depedent inhibition of mTORC1.nStructure/function analyses have led us to identify two segments in REDD1 that are essential for function,nwhich act in an interdependent manner. We have determined a crystal structure of REDD1 at 2.0 Anresolution, which shows that these two segments fold together to forman intact domain with a novel fold. Thisndomain is characterized by an R/β sandwich consisting of two antiparallel R-helices and a mixed β-sheetnencompassing an uncommon psi-loop motif. Structure-based docking and functional analyses suggest thatnREDD1 does not directly bind to 14-3-3 proteins. Sequence conservation mapping to the surface of thenstructure and mutagenesis studies demarcated a hotspot likely to interact with effector proteins that isnessential for REDD1-mediated mTORC1 inhibition.
机译：REDD1是一种保守的应激反应蛋白，可调节mTORC1，mTORC1是与癌症有关的细胞生长和增殖的关键调节剂。 REDD1是由缺氧诱导的，REDD1的过表达足以抑制mTORC1。 mTORC1受小GTPase Rheb的调控，而后者又受GTPase活化蛋白复合物TSC1 / TSC2的调控。 REDD1诱导的mTORC1n抑制作用需要TSC1 / TSC2复合物，而REDD1已被提出通过直接结合吨蛋白并将14-3-3蛋白质从TSC2中分离出来而起作用，从而导致对tTOR2的mTORC1抑制作用.n结构/功能分析已使我们确定REDD1中的两个对功能必不可少的部分，它们以相互依赖的方式起作用。我们已经确定了REDD1在2.0 Anresolution的晶体结构，该结构表明这两个片段以新的折叠方式折叠在一起形成了完整的结构域。该n结构域的特征在于R /β夹心结构，其由两个反平行的R-螺旋和包含罕见的psi-环基序的混合β-片状蛋白组成。基于结构的对接和功能分析表明，nREDD1不直接结合14-3-3蛋白。序列保守性映射到随后的结构和诱变研究的表面，划定了一个热点，该热点可能与效应蛋白相互作用，该效应蛋白对于REDD1介导的mTORC1抑制至关重要。

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