Department of Biochemistry, McGill University, Montréal, Québec, Canada.
Mol Cell. 2009 Dec 25;36(6):1034-47. doi: 10.1016/j.molcel.2009.11.021.
Mutations in the parkin gene are responsible for a common inherited form of Parkinson's disease (PD). Parkin is a RING-type E3 ubiquitin ligase with an N-terminal ubiquitin-like domain (Ubl). We report here that the parkin Ubl binds SH3 domains from endocytic BAR proteins such as endophilin-A with an affinity comparable to proline-rich domains (PRDs) from well-established SH3 partners. The NMR structure of the Ubl-SH3 complex identifies the PaRK extension, a unique C-terminal motif in the parkin Ubl required for SH3 binding and for parkin-mediated ubiquitination of endophilin-A in vitro. In nerve terminals, conditions that promote phosphorylation enhance the interaction between parkin and endophilin-A and increase the levels of ubiquitinated proteins within PRD-associated synaptic protein complexes in wild-type but not parkin knockout brain. The findings identify a pathway for the recruitment of synaptic substrates to parkin with the potential to explain the defects in synaptic transmission observed in recessive forms of PD.
帕金森病（PD）的一种常见遗传形式是由 parkin 基因突变引起的。Parkin 是一种具有 N 端泛素样结构域（Ubl）的 RING 型 E3 泛素连接酶。我们在此报告，parkin Ubl 与内吞 BAR 蛋白（如内吞素-A）的 SH3 结构域结合，亲和力可与来自成熟 SH3 伴侣的富含脯氨酸结构域（PRD）相媲美。Ubl-SH3 复合物的 NMR 结构确定了 PaRK 延伸，这是 parkin Ubl 中独特的 C 末端基序，对于 SH3 结合和 parkin 介导的内吞素-A 在体外的泛素化是必需的。在神经末梢，促进磷酸化的条件增强了 parkin 和内吞素-A 之间的相互作用，并增加了野生型而非 parkin 敲除脑内 PRD 相关突触蛋白复合物中泛素化蛋白的水平。这些发现确定了将突触底物募集到 parkin 的途径，这有可能解释在隐性 PD 形式中观察到的突触传递缺陷。
