Structure of phosphorylated UBL domain and insights into PINK1-orchestrated parkin activation
Structure of phosphorylated UBL domain and insights into PINK1-orchestrated parkin activation
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DOI：
10.1073/pnas.1613040114
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发表时间：
2017-01-10
影响因子：
11.1
通讯作者：
Shaw, Gary S.
中科院分区：
文献类型：
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作者：
Aguirre, Jacob D.;Dunkerley, Karen M.;Shaw, Gary S.
PARK 2和PARK 6基因的突变是大多数遗传性帕金森病病例的原因。这些基因分别编码E3泛素连接酶parkin和蛋白激酶PTEN诱导的激酶1（PINK 1）。parkin和PINK 1共同调节线粒体自噬途径，该途径在氧化应激后修复受损的线粒体。天然parkin是无活性的，并存在于由其泛素样（UBL）结构域介导的自抑制状态。PINK 1磷酸化的丝氨酸65在帕金的UBL和丝氨酸65的泛素完全激活泛素连接酶的活性，然而，这些观察结果的结构原理尚不清楚。在这里，我们报告的磷酸化的UBL结构域从帕金。我们发现，不稳定的UBL的结果从重排到疏水核心包装，修改其结构。改变表面静电从磷酸丝氨酸组破坏其分子内的协会，导致在磷酸化帕金较差的自抑制。此外，我们表明，磷酸化的UBL结构域和泛素需要激活帕金释放的UBL结构域，形成一个扩展的结构，需要促进E2-泛素结合。总之，这些结果强调了PINK 1磷酸化信号激活帕金蛋白的重要性，并提供了帕金蛋白泛素连接酶潜力解开的结构图。
Mutations in PARK2 and PARK6 genes are responsible for the majority of hereditary Parkinson's disease cases. These genes encode the E3 ubiquitin ligase parkin and the protein kinase PTEN-induced kinase 1 (PINK1), respectively. Together, parkin and PINK1 regulate the mitophagy pathway, which recycles damaged mitochondria following oxidative stress. Native parkin is inactive and exists in an autoinhibited state mediated by its ubiquitin-like (UBL) domain. PINK1 phosphorylation of serine 65 in parkin's UBL and serine 65 of ubiquitin fully activate ubiquitin ligase activity; however, a structural rationale for these observations is not clear. Here, we report the structure of the phosphorylated UBL domain from parkin. We find that destabilization of the UBL results from rearrangements to hydrophobic core packing that modify its structure. Altered surface electrostatics from the phosphoserine group disrupt its intramolecular association, resulting in poorer autoinhibition in phosphorylated parkin. Further, we show that phosphorylation of both the UBL domain and ubiquitin are required to activate parkin by releasing the UBL domain, forming an extended structure needed to facilitate E2-ubiquitin binding. Together, the results underscore the importance of parkin activation by the PINK1 phosphorylation signal and provide a structural picture of the unraveling of parkin's ubiquitin ligase potential.