Department of Biology, Institute of Molecular Biology and Biophysics, ETH Zurich, 8093 Zurich, Switzerland.
Department of Biology, Molecular Microbiology, University of Konstanz, 78457 Konstanz, Germany.
Science. 2022 Feb 25;375(6583):839-844. doi: 10.1126/science.abl6459. Epub 2022 Feb 24.
The nascent polypeptide-associated complex (NAC) interacts with newly synthesized proteins at the ribosomal tunnel exit and competes with the signal recognition particle (SRP) to prevent mistargeting of cytosolic and mitochondrial polypeptides to the endoplasmic reticulum (ER). How NAC antagonizes SRP and how this is overcome by ER targeting signals are unknown. Here, we found that NAC uses two domains with opposing effects to control SRP access. The core globular domain prevented SRP from binding to signal-less ribosomes, whereas a flexibly attached domain transiently captured SRP to permit scanning of nascent chains. The emergence of an ER-targeting signal destabilized NAC's globular domain and facilitated SRP access to the nascent chain. These findings elucidate how NAC hands over the signal sequence to SRP and imparts specificity of protein localization.
新生多肽相关复合物（NAC）与核糖体隧道出口处新合成的蛋白质相互作用，并与信号识别颗粒（SRP）竞争，以防止细胞质和线粒体多肽错误靶向内质网（ER）。NAC 如何拮抗 SRP，以及 ER 靶向信号如何克服这一点尚不清楚。在这里，我们发现 NAC 使用两个具有相反作用的结构域来控制 SRP 的进入。核心球状结构域阻止 SRP 与无信号核糖体结合，而灵活连接的结构域则暂时捕获 SRP，以允许新生链的扫描。ER 靶向信号的出现使 NAC 的球状结构域不稳定，并促进了 SRP 对新生链的进入。这些发现阐明了 NAC 如何将信号序列传递给 SRP，并赋予蛋白质定位的特异性。
