德国康斯坦茨大学Elke Deuerling、瑞士苏黎世联邦理工学院Nenad Ban和美国加州理工学院Shu-ou Sha研究组合作取得最新进展。他们揭示内质网 (ER)蛋白靶向过程中核糖体上从新生多肽相关复合物 (NAC)到信号识别粒子 (SRP)的信号序列切换机制。这一研究成果于2022年2月25日发表在国际顶尖学术期刊《科学》上。

他们发现 NAC 使用两个具有相反效果的结构域来控制 SRP 访问。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瞬时捕获 SRP 以允许扫描新生链。 ER 靶向信号的出现破坏了 NAC 的球状结构域并促进了 SRP 进入新生链。这些发现阐明了 NAC 如何将信号序列移交给 SRP 并赋予蛋白质定位的特异性。

据悉，NAC在核糖体隧道出口处与新合成的蛋白质相互作用，并与SRP竞争，以防止细胞溶质和线粒体多肽错误靶向ER。NAC 如何拮抗 SRP 以及如何通过 ER 靶向信号克服这一点尚不清楚。

附：英文原文

Title: Mechanism of signal sequence handover from NAC to SRP on ribosomes during ER-protein targeting

Author: Ahmad Jomaa, Martin Gamerdinger, Hao-Hsuan Hsieh, Annalena Wallisch, Viswanathan Chandrasekaran, Zeynel Ulusoy, Alain Scaiola, Ramanujan S. Hegde, Shu-ou Shan, Nenad Ban, Elke Deuerling

Issue&Volume: 2022-02-25

Abstract: 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.

DOI: abl6459

Source: https://www.science.org/doi/10.1126/science.abl6459