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DCNL1 Functions as a Substrate Sensor and Activator of Cullin 2-RING Ligase

机译：DCNL1用作Cullin 2-RING连接酶的底物传感器和激活剂

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Substrate engagement by F-box proteins promotes NEDD8 modification of cullins, which is necessary for the activation of cullin-RING E3 ubiquitin ligases (CRLs). However, the mechanism by which substrate recruitment triggers cullin neddylation remains unclear. Here, we identify DCNL1 (defective in cullin neddylation 1-like 1) as a component of CRL2 called ECV (elongins BC/CUL2/VHL) and show that molecular suppression of DCNL1 attenuates CUL2 neddylation. DCNL1 via its DAD patch binds to CUL2 but is also able to bind VHL independent of CUL2 and the DAD patch. The engagement of the substrate hypoxia-inducible factor 1α (HIF1α) to the substrate receptor VHL increases DCNL1 binding to VHL as well as to CUL2. Notably, an engineered mutant form of HIF1α that associates with CUL2, but not DCNL1, fails to trigger CUL2 neddylation and retains ECV in an inactive state. These findings support a model in which substrate engagement prompts DCNL1 recruitment that facilitates the initiation of CUL2 neddylation and define DCNL1 as a “substrate sensor switch” for ECV activation.
机译：F-box蛋白与底物的结合促进了cullins的NEDD8修饰，这对于激活cullin-RING E3泛素连接酶（CRLs）是必需的。但是，底物募集引发cullin消融的机制仍不清楚。在这里，我们将DCNL1（在cullin融合作用1样1中有缺陷）确定为称为ECV（延伸蛋白BC / CUL2 / VHL）的CRL2的组成部分，并显示DCNL1的分子抑制作用减弱了CUL2融合作用。 DCNL1通过其DAD修补程序绑定到CUL2，但也能够独立于CUL2和DAD修补程序绑定VHL。底物缺氧诱导因子1α（HIF1α）与底物受体VHL的结合增加了DCNL1与VHL和CUL2的结合。值得注意的是，与CUL2关联但与DCNL1关联的HIF1α的工程突变体形式无法触发CUL2的二烯化作用，并使ECV保持非活动状态。这些发现支持了一个模型，在该模型中，底物的参与促使DCNL1募集，这促进了CUL2融合的启动，并将DCNL1定义为ECV激活的“底物传感器开关”。

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