Department of Biochemistry, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada N6A 5C1.
Nat Commun. 2013;4:1983. doi: 10.1038/ncomms2983.
Mutations in the park2 gene, encoding the RING-inBetweenRING-RING E3 ubiquitin ligase parkin, cause 50% of autosomal recessive juvenile Parkinsonism cases. More than 70 known pathogenic mutations occur throughout parkin, many of which cluster in the inhibitory amino-terminal ubiquitin-like domain, and the carboxy-terminal RING2 domain that is indispensable for ubiquitin transfer. A structural rationale showing how autosomal recessive juvenile Parkinsonism mutations alter parkin function is still lacking. Here we show that the structure of parkin RING2 is distinct from canonical RING E3 ligases and lacks key elements required for E2-conjugating enzyme recruitment. Several pathogenic mutations in RING2 alter the environment of a single surface-exposed catalytic cysteine to inhibit ubiquitination. Native parkin adopts a globular inhibited conformation in solution facilitated by the association of the ubiquitin-like domain with the RING-inBetweenRING-RING C-terminus. Autosomal recessive juvenile Parkinsonism mutations disrupt this conformation. Finally, parkin autoubiquitinates only in cis, providing a molecular explanation for the recessive nature of autosomal recessive juvenile Parkinsonism.
Park2 基因突变，Park2 基因编码 RING-in-Between-RING-RING E3 泛素连接酶 parkin，导致 50%的常染色体隐性遗传少年型帕金森病病例。超过 70 种已知的致病性突变发生在 parkin 全身，其中许多突变聚集在抑制性氨基末端泛素样结构域和羧基末端 RING2 结构域，该结构域对于泛素转移是必不可少的。缺乏一个显示常染色体隐性遗传少年型帕金森病突变如何改变 parkin 功能的结构基础。在这里，我们显示 parkin RING2 的结构与典型的 RING E3 连接酶不同，并且缺乏招募 E2 连接酶所必需的关键元件。RING2 中的几个致病性突变改变了单个表面暴露的催化半胱氨酸的环境，从而抑制泛素化。天然 parkin 在溶液中采用球形抑制构象，这是由泛素样结构域与 RING-in-Between-RING-RING C 末端的关联促成的。常染色体隐性遗传少年型帕金森病突变破坏了这种构象。最后，parkin 仅在顺式自动泛素化，为常染色体隐性遗传少年型帕金森病的隐性性质提供了分子解释。
