文章：

模板驱动的SCF^FBXO42支架调控PP2A降解

Template-driven scaffolding of SCF^FBXO42 regulates PP2A degradation

原文发布日期：2026-04-15

DOI: 10.1038/s41586-026-10368-z

类型: Article

开放获取: 是

英文摘要：

Protein phosphatase 2A (PP2A) is a Ser/Thr phosphatase that regulates the phosphorylation of almost all cellular processes, including cell division and proliferation1,2. PP2A forms heterotrimeric holoenzyme complexes comprising a catalytic subunit (PP2Ac), a scaffolding subunit (PP2Aa) and variable B regulatory subunits that exert precise control over enzyme substrate specificity and prevent indiscriminate dephosphorylation of phosphoproteins3. However, the mechanisms that control the activity of uncomplexed catalytic subunits have remained relatively unclear. Here we find that the E3 ligase SKP1–CUL1–F-box (SCF) complex containing F-box other protein 42 (FBXO42, also known as JFK; hereafter, SCFFBXO42) degrades holoenzyme-free PP2Ac in a complex with the coiled-coil protein CCDC6 to maintain cancer cell fitness. The cryo-electron microscopy structure of the FBXO42–CCDC6–PP2Ac assembly reveals a pseudosymmetric architecture in which CCDC6 forms a central dimeric template that recruits multiple copies of PP2Ac and creates a substrate for FBXO42. Both the quaternary structure of this CCDC6–PP2Ac heterodimer and the post-translationally methylated tail of PP2Ac are recognized by FBXO42 for ubiquitination. The multivalent structure facilitated by CCDC6 enables the assembly of multiple degradation complexes along a single coiled coil, leading to the turnover of free phosphatases and downregulation of catalytic activity. Together, our findings define a mechanism for PP2A control through the ubiquitin-proteosome system and establish a paradigm for cullin-RING ligase–substrate interactions.

摘要翻译： 

蛋白磷酸酶2A（PP2A）是一种丝氨酸/苏氨酸磷酸酶，调控几乎所有细胞进程（包括细胞分裂和增殖）中的蛋白质磷酸化水平1,2。PP2A形成异源三聚体全酶复合物，由催化亚基（PP2Ac）、支架亚基（PP2Aa）和可变B调节亚基组成，后者可精确控制酶底物特异性并防止磷蛋白的非特异性去磷酸化3。然而，调控游离催化亚基活性的机制仍相对不清楚。本研究发现，含F-box其他蛋白42（FBXO42，也称JFK）的E3连接酶SKP1–CUL1–F-box（SCF）复合物（以下简称SCFFBXO42）通过与卷曲螺旋蛋白CCDC6形成复合物，降解不含全酶组分的PP2Ac，从而维持癌细胞适应性。FBXO42–CCDC6–PP2Ac复合物的冷冻电镜结构揭示了一种伪对称结构：CCDC6形成中心二聚化模板，招募多拷贝PP2Ac并构建FBXO42的底物。CCDC6–PP2Ac异源二聚体的四级结构以及PP2Ac的翻译后甲基化尾部均可被FBXO42识别以实现泛素化。由CCDC6介导的多价结构使得多个降解复合物能沿单一卷曲螺旋进行组装，从而促进游离磷酸酶的周转并下调其催化活性。综上所述，本研究阐明了通过泛素-蛋白酶体系统调控PP2A的机制，并为cullin-RING连接酶与底物的相互作用建立了范式。

原文链接：

Template-driven scaffolding of SCF^FBXO42 regulates PP2A degradation