A ribosome-associated chaperone enables substrate triage in a cotranslational protein targeting complex.
A ribosome-associated chaperone enables substrate triage in a cotranslational protein targeting complex.
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DOI：
10.1038/s41467-020-19548-5
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发表时间：
2020-11-17
影响因子：
16.6
通讯作者：
Shan SO
中科院分区：
文献类型：
--
作者：
Hsieh HH;Lee JH;Chandrasekar S;Shan SO
蛋白质生物合成在所有细胞中都是必不可少的，并且当新生多肽从核糖体出口通道出现时启动，其中多个核糖体相关蛋白质生物合成因子（RPB）将新生蛋白质引导到不同的命运。不同的RPB如何在时空上相互协调以影响精确的蛋白质生物合成是一个新出现的问题。在这里，我们解决这个问题，通过研究的作用，共翻译分子伴侣，新生的多肽相关复合物（NAC），在调节底物选择信号识别颗粒（SRP），一个普遍保守的蛋白质靶向机器。我们发现，哺乳动物SRP和SRP受体（SR）是不足以产生生物学所需的特异性蛋白质靶向内质网。NAC与核糖体上的SRP共结合并重塑其构象景观，以调节其与SR的相互作用动力学，从而减少无信号核糖体的非特异性靶向和具有短新生链的核糖体的抢先靶向。数学模型表明，NAC诱导的SRP活性的调节是必不可少的共翻译蛋白质靶向的保真度。我们的工作建立了一个分子模型，NAC如何作为一个分流因子，以防止蛋白质的错误定位，并演示了如何在核糖体出口位点的RPB的大分子拥挤提高了保真度的底物选择到个别蛋白质的生物合成途径。生物化学结合生物物理测量和数学建模提供了深入了解共翻译伴侣，新生多肽相关复合物（NAC），通过信号识别颗粒（SRP）调节底物选择，并减少异常的，非特异性的核糖体靶向ER的机制。
Protein biogenesis is essential in all cells and initiates when a nascent polypeptide emerges from the ribosome exit tunnel, where multiple ribosome-associated protein biogenesis factors (RPBs) direct nascent proteins to distinct fates. How distinct RPBs spatiotemporally coordinate with one another to affect accurate protein biogenesis is an emerging question. Here, we address this question by studying the role of a cotranslational chaperone, nascent polypeptide-associated complex (NAC), in regulating substrate selection by signal recognition particle (SRP), a universally conserved protein targeting machine. We show that mammalian SRP and SRP receptors (SR) are insufficient to generate the biologically required specificity for protein targeting to the endoplasmic reticulum. NAC co-binds with and remodels the conformational landscape of SRP on the ribosome to regulate its interaction kinetics with SR, thereby reducing the nonspecific targeting of signalless ribosomes and pre-emptive targeting of ribosomes with short nascent chains. Mathematical modeling demonstrates that the NAC-induced regulations of SRP activity are essential for the fidelity of cotranslational protein targeting. Our work establishes a molecular model for how NAC acts as a triage factor to prevent protein mislocalization, and demonstrates how the macromolecular crowding of RPBs at the ribosome exit site enhances the fidelity of substrate selection into individual protein biogenesis pathways. Biochemistry combined with biophysical measurements and mathematical modeling offer insight into the mechanism by which the cotranslational chaperone, nascent polypeptide-associated complex (NAC), modulates substrate selection by signal recognition particle (SRP) and reduces aberrant, nonspecific targeting of ribosomes to the ER.
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影响因子：
14.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Bacher, G;Lutcke, H;Dobberstein, B
通讯作者：
Dobberstein, B
影响因子：
64.5
作者：
GORLICH, D;RAPOPORT, TA
通讯作者：
RAPOPORT, TA
影响因子：
16
作者：
Gamerdinger, Martin;Kobayashi, Kan;Deuerling, Elke
通讯作者：
Deuerling, Elke
影响因子：
64.5
作者：
JUNGNICKEL, B;RAPOPORT, TA
通讯作者：
RAPOPORT, TA