Structural analysis and functional implications of the negative mTORC1 regulator REDD1.
Structural analysis and functional implications of the negative mTORC1 regulator REDD1.
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DOI：
10.1021/bi902135e
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发表时间：
2010-03-23
期刊：
影响因子：
2.9
通讯作者：
Zhang, Xuewu
中科院分区：
文献类型：
--
作者：
Vega-Rubin-de-Celis, Silvia;Abdallah, Zeina;Kinch, Lisa;Grishin, Nick V.;Brugarolas, James;Zhang, Xuewu
REDD1是一种保守的应激反应蛋白，可调节mTORC1，而mTORC1是与癌症有关的细胞生长和增殖的关键调节因子。REDD1是由缺氧诱导的，并且REDD1过表达足以抑制mTORC1。mTORC1受小GTPase Rheb调控，而后者又受GTPase激活蛋白复合物TSC1/TSC2调控。REDD1诱导的mTORC1抑制需要TSC1/TSC2复合物，并且已经提出REDD1通过直接结合并隔离14-3-3蛋白远离TSC2导致mTORC1依赖于TSC2的抑制而起作用。结构/功能分析使我们确定了REDD1中对功能至关重要的两个片段，它们以相互依赖的方式起作用。我们在2.0 Å分辨率下确定了REDD1的晶体结构，这表明这两个片段折叠在一起形成一个具有新褶皱的完整结构域。该结构域的特征是由两个反平行的α-螺旋组成的α/β三明治和一个包含不常见的psi-loop基序的混合β片。基于结构的对接和功能分析表明，REDD1不直接结合14-3-3蛋白。序列保守映射到结构表面和诱变研究划定了一个可能与效应蛋白相互作用的热点，这对于redd1介导的mTORC1抑制至关重要。
REDD1 is a conserved stress-response protein that regulates mTORC1, a critical regulator of cell growth and proliferation that is implicated in cancer. REDD1 is induced by hypoxia and REDD1 overexpression is sufficient to inhibit mTORC1. mTORC1 is regulated by the small GTPase Rheb, which in turn is regulated by the GTPase-activating protein complex, TSC1/TSC2. REDD1 induced-mTORC1 inhibition requires the TSC1/TSC2 complex, and REDD1 has been proposed to act by directly binding to and sequestering 14-3-3 proteins away from TSC2 leading to TSC2-depedent inhibition of mTORC1. Structure/function analyses have led us to identify two segments in REDD1 that are essential for function, which act in an interdependent manner. We have determined a crystal structure of REDD1 at 2.0 Å resolution, which shows that these two segments fold together to form an intact domain with a novel fold. This domain is characterized by an α/β sandwich consisting of two antiparallel α-helices and a mixed β-sheet encompassing an uncommon psi-loop motif. Structure-based docking and functional analyses suggest that REDD1 does not directly bind to 14-3-3 proteins. Sequence conservation mapping to the surface of the structure and mutagenesis studies demarcated a hotspot likely to interact with effector proteins that is essential for REDD1-mediated mTORC1 inhibition.
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影响因子：
64.5
作者：
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通讯作者：
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DOI：
10.1093/bioinformatics/8.3.275
发表时间：
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期刊：
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影响因子：
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DOI：
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发表时间：
2005-08-09
期刊：
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影响因子：
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作者：
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通讯作者：
Moorhead, Greg B G
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
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作者：
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通讯作者：
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