Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Nat Struct Mol Biol. 2020 Jun;27(6):550-560. doi: 10.1038/s41594-020-0424-6. Epub 2020 May 11.
The interplay between E2 and E3 enzymes regulates the polyubiquitination of substrates in eukaryotes. Among the several RING-domain E3 ligases in humans, many utilize two distinct E2s for polyubiquitination. For example, the cell cycle regulatory E3, human anaphase-promoting complex/cyclosome (APC/C), relies on UBE2C to prime substrates with ubiquitin (Ub) and on UBE2S to extend polyubiquitin chains. However, the potential coordination between these steps in ubiquitin chain formation remains undefined. While numerous studies have unveiled how RING E3s stimulate individual E2s for Ub transfer, here we change perspective to describe a case where the chain-elongating E2 UBE2S feeds back and directly stimulates the E3 APC/C to promote substrate priming and subsequent multiubiquitination by UBE2C. Our work reveals an unexpected model for the mechanisms of RING E3-dependent ubiquitination and for the diverse and complex interrelationship between components of the ubiquitination cascade.
E2 和 E3 酶之间的相互作用调节真核生物中底物的多泛素化。在人类的几种 RING 结构域 E3 连接酶中，许多酶利用两种不同的 E2 进行多泛素化。例如，细胞周期调节 E3、人有丝分裂促进复合物/环体（APC/C），依赖于 UBE2C 用泛素（Ub）对底物进行引发，依赖于 UBE2S 来延长多泛素链。然而，在泛素链形成中这些步骤之间的潜在协调仍未定义。虽然许多研究已经揭示了 RING E3 如何刺激单个 E2 进行 Ub 转移，但在这里，我们改变视角来描述一个情况，即链延伸 E2 UBE2S 反馈并直接刺激 E3 APC/C 以促进 UBE2C 对底物的引发和随后的多泛素化。我们的工作揭示了 RING E3 依赖性泛素化的机制以及泛素化级联组件之间多样且复杂的相互关系的一个意外模型。
