Woelk Tanja, Oldrini Barbara, Maspero Elena, Confalonieri Stefano, Cavallaro Elena, Di Fiore Pier Paolo, Polo Simona
IFOM, The FIRC Institute for Molecular Oncology, Via Adamello 16, 20139, Milan, Italy.
Nat Cell Biol. 2006 Nov;8(11):1246-54. doi: 10.1038/ncb1484. Epub 2006 Oct 1.
Many proteins contain ubiquitin-binding domains or motifs (UBDs), such as the UIM (ubiquitin-interacting motif) and are referred to as ubiquitin receptors. Ubiquitin receptors themselves are frequently monoubiquitinated by a process that requires the presence of a UBD and is referred to as coupled monoubiquitination. Using a UIM-containing protein, eps15, as a model, we show here that coupled monoubiquitination strictly depends on the ability of the UIM to bind to monoubiquitin (mUb). We found that the underlying molecular mechanism is based on interaction between the UIM and a ubiquitin ligase (E3), which has itself been modified by ubiquitination. Furthermore, we demonstrate that the in vivo ubiquitination of members of the Nedd4 family of E3 ligases correlates with their ability to monoubiquitinate eps15. Thus, our results clarify the mechanism of coupled monoubiquitination and identify the ubiquitination of E3 ligases as a critical determinant in this process.
许多蛋白质含有泛素结合结构域或基序（UBDs），如泛素相互作用基序（UIM），这些蛋白质被称为泛素受体。泛素受体本身经常通过一个需要UBD存在的过程发生单泛素化，这个过程被称为偶联单泛素化。我们以含有UIM的蛋白质eps15为模型，在此表明偶联单泛素化严格依赖于UIM与单泛素（mUb）结合的能力。我们发现其潜在的分子机制基于UIM与一种已被泛素化修饰的泛素连接酶（E3）之间的相互作用。此外，我们证明E3连接酶Nedd4家族成员的体内泛素化与其单泛素化eps15的能力相关。因此，我们的结果阐明了偶联单泛素化的机制，并确定E3连接酶的泛素化是这一过程中的关键决定因素。
