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 PARKIN 和PINK1這一對酶之所以引人矚目，不僅是因?yàn)樗鼈冋{(diào)控線粒體自噬過程(細(xì)胞通過該過程降解其受損的線粒體)，而且是因?yàn)樗鼈冊凇俺Ｈ旧w隱性遺傳性青少年型帕金森氏癥” (AR-JP)中是突變的。在分子層面上，PINK1通過將 PARKIN與泛素(Ub)相似的(Ubl)區(qū)域和Ub分子都磷酸化來激發(fā)PARKIN。David Komander 及同事揭示了導(dǎo)致由phosphoUb誘導(dǎo)的PARKIN激發(fā)的構(gòu)形變化，同時也揭示了PARKIN是怎樣將phosphoUb鏈招募到線粒體上的。PARKIN在與phosphoUb所形成復(fù)合物中的晶體結(jié)構(gòu)也表明，PARKIN內(nèi)供phosphoUb結(jié)合的結(jié)合穴攜帶在AR-JP患者中發(fā)生突變的氨基酸殘基。

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.