共衔接子驱动 CUL3 E3 连接酶复合物的组装。
Co-adaptor driven assembly of a CUL3 E3 ligase complex.
机构信息
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley CA 94720, USA.
Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley CA 94720, USA; Howard Hughes Medical Institute, University of California at Berkeley, Berkeley CA 94720, USA; Quantitative Biosciences Institute, QB3, University of California at Berkeley, Berkeley CA 94720, USA.
出版信息
Mol Cell. 2022 Feb 3;82(3):585-597.e11. doi: 10.1016/j.molcel.2022.01.004.
Cullin-RING E3 ligases (CRLs) are essential ubiquitylation enzymes that combine a catalytic core built around cullin scaffolds with ∼300 exchangeable substrate adaptors. To ensure robust signal transduction, cells must constantly form new CRLs by pairing substrate-bound adaptors with their cullins, but how this occurs at the right time and place is still poorly understood. Here, we show that formation of individual CRL complexes is a tightly regulated process. Using CUL3 as a model, we found that its co-adaptor PEF1-ALG2 initiates CRL3 formation by releasing KLHL12 from an assembly inhibitor at the endoplasmic reticulum, before co-adaptor monoubiquitylation stabilizes the enzyme for substrate modification. As the co-adaptor also helps recruit substrates, its role in CRL assembly couples target recognition to ubiquitylation. We propose that regulators dedicated to specific CRLs, such as assembly inhibitors or co-adaptors, cooperate with target-agnostic adaptor exchange mechanisms to establish E3 ligase complexes that control metazoan development.
Cullin-RING E3 连接酶（CRLs）是一种必需的泛素化酶，它将围绕 cullin 支架构建的催化核心与约 300 个可交换的底物衔接子结合在一起。为了确保稳健的信号转导，细胞必须通过将结合底物的衔接子与它们的 cullin 配对，不断形成新的 CRL，但这在何时以及何地发生仍知之甚少。在这里，我们表明，单个 CRL 复合物的形成是一个受到严格调控的过程。我们以 CUL3 作为模型，发现其共同衔接子 PEF1-ALG2 通过在 ER 上将 KLHL12 从组装抑制剂中释放出来，从而启动 CRL3 的形成，然后共同衔接子单泛素化稳定酶以进行底物修饰。由于共同衔接子还有助于招募底物，因此其在 CRL 组装中的作用将靶标识别与泛素化偶联在一起。我们提出，专门针对特定 CRL 的调节剂，如组装抑制剂或共同衔接子，与目标不可知的衔接子交换机制合作，以建立控制后生动物发育的 E3 连接酶复合物。
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