近日，英国邓迪大学Yogesh Kulathu等研究人员合作发现，UFM1 E3连接酶识别并释放ER易位子中的60S核糖体。相关论文于2024年2月21日在线发表在《自然》杂志上。

研究人员表示，停滞在内质网（ER）上的核糖体会被60S核糖体亚基蛋白RPL26（又称uL24）上的泛素样蛋白UFM1共价修饰。这种被称为UFMylation的修饰是由UFM1核糖体E3连接酶（UREL）复合物协调的，该复合物由UFL1、UFBP1和CDK5RAP3组成。然而，UREL的催化机理和UFMylation的功能性后果尚不清楚。

研究人员展示了UREL与60S核糖体结合的冷冻电镜结构，揭示了其底物特异性的基础。UREL缠绕在60S亚基上，形成一个C形钳夹结构，一端阻断了tRNA结合位点，另一端阻断了多肽出口隧道。UFL1环插入并重塑肽基转移酶中心。UREL的这些特征表明，UFMylation在从ER膜释放和再循环停滞或终止的核糖体方面发挥着关键作用。在缺乏功能性UREL的情况下，60S-SEC61转座子复合物会在ER膜上聚集，这表明UFMylation对于SEC61从60S亚基中释放是必要的。值得注意的是，UREL从“书写者”向“阅读者”模块的功能转换促进了这种释放，UREL可识别其产物——UFMylated 60S核糖体。总之，研究人员确定了UREL在将60S亚基从SEC61异位子中分离出来方面的基本作用，以及UFMylation在调节ER蛋白质平衡方面的基础。

附：英文原文

Title: The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons

Author: Makhlouf, Linda, Peter, Joshua J., Magnussen, Helge M., Thakur, Rohan, Millrine, David, Minshull, Thomas C., Harrison, Grace, Varghese, Joby, Lamoliatte, Frederic, Foglizzo, Martina, Macartney, Thomas, Calabrese, Antonio N., Zeqiraj, Elton, Kulathu, Yogesh

Issue&Volume: 2024-02-21

Abstract: Stalled ribosomes at the endoplasmic reticulum (ER) are covalently modified with the ubiquitin-like protein UFM1 on the 60S ribosomal subunit protein RPL26 (also known as uL24)1,2. This modification, which is known as UFMylation, is orchestrated by the UFM1 ribosome E3 ligase (UREL) complex, comprising UFL1, UFBP1 and CDK5RAP3 (ref. 3). However, the catalytic mechanism of UREL and the functional consequences of UFMylation are unclear. Here we present cryo-electron microscopy structures of UREL bound to 60S ribosomes, revealing the basis of its substrate specificity. UREL wraps around the 60S subunit to form a C-shaped clamp architecture that blocks the tRNA-binding sites at one end, and the peptide exit tunnel at the other. A UFL1 loop inserts into and remodels the peptidyl transferase centre. These features of UREL suggest a crucial function for UFMylation in the release and recycling of stalled or terminated ribosomes from the ER membrane. In the absence of functional UREL, 60S–SEC61 translocon complexes accumulate at the ER membrane, demonstrating that UFMylation is necessary for releasing SEC61 from 60S subunits. Notably, this release is facilitated by a functional switch of UREL from a ‘writer’ to a ‘reader’ module that recognizes its product—UFMylated 60S ribosomes. Collectively, we identify a fundamental role for UREL in dissociating 60S subunits from the SEC61 translocon and the basis for UFMylation in regulating protein homeostasis at the ER.

DOI: 10.1038/s41586-024-07093-w

Source: https://www.nature.com/articles/s41586-024-07093-w