PARKIN 和PINK1这一对酶之所以引人瞩目，不仅是因为它们调控线粒体自噬过程(细胞通过该过程降解其受损的线粒体)，而且是因为它们在“常染色体隐性遗传性青少年型帕金森氏症” (AR-JP)中是突变的。在分子层面上，PINK1通过将 PARKIN与泛素(Ub)相似的(Ubl)区域和Ub分子都磷酸化来激发PARKIN。David Komander 及同事揭示了导致由phosphoUb诱导的PARKIN激发的构形变化，同时也揭示了PARKIN是怎样将phosphoUb链招募到线粒体上的。PARKIN在与phosphoUb所形成复合物中的晶体结构也表明，PARKIN内供phosphoUb结合的结合穴携带在AR-JP患者中发生突变的氨基酸残基。

原文摘要:

The E3 ubiquitin ligase PARKIN (encoded by PARK2) and the protein kinase PINK1 (encoded byPARK6) are mutated in autosomal-recessive juvenile Parkinsonism (AR-JP) and work together in the disposal of damaged mitochondria by mitophagy. PINK1 is stabilized on the outside of depolarized mitochondria and phosphorylates polyubiquitin as well as the PARKIN ubiquitin-like (Ubl) domain9, 10. These phosphorylation events lead to PARKIN recruitment to mitochondria, and activation by an unknown allosteric mechanism. Here we present the crystal structure of Pediculus humanus PARKIN in complex with Ser65-phosphorylated ubiquitin (phosphoUb), revealing the molecular basis for PARKIN recruitment and activation. The phosphoUb binding site on PARKIN comprises a conserved phosphate pocket and harbours residues mutated in patients with AR-JP. PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN. Moreover, phosphoUb-mediated Ubl release enhances Ubl phosphorylation by PINK1, leading to conformational changes within the Ubl domain and stabilization of an open, active conformation of PARKIN. We redefine the role of the Ubl domain not only as an inhibitory13 but also as an activating element that is restrained in inactive PARKIN and released by phosphoUb. Our work opens up new avenues to identify small-molecule PARKIN activators.