Structural determinants of PINK1 topology and dual subcellular distribution.
Structural determinants of PINK1 topology and dual subcellular distribution.
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DOI：
10.1186/1471-2121-11-90
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发表时间：
2010-11-22
期刊：
影响因子：
--
通讯作者：
Kang UJ
中科院分区：
文献类型：
--
作者：
Lin W;Kang UJ
PINK1是一种线粒体靶向的激酶，它结构性地定位于线粒体和胞浆。PINK1在线粒体加工后如何实现胞浆定位的机制尚不清楚。了解PINK1的亚细胞定位将使我们深入了解PINK1的功能以及PINK1突变是如何导致帕金森病的。我们询问了线粒体定位信号、跨膜结构域和激酶结构域如何参与PINK1的定位。我们证实了PINK1线粒体靶向信号与线粒体定位有关。一旦进入线粒体，我们发现PINK1跨膜和激酶结构域对于膜系留和面向胞浆的拓扑结构都是重要的。我们还发现，PINK1的双重亚细胞分布既需要Hsp90与激酶域的相互作用，也需要跨膜域下游的裂解位点的蛋白分解，因为该裂解位点的去除完全取消了胞内的PINK1。此外，Hsp90-PINK1相互作用的中断增加了线粒体PINK1的水平。综上所述，我们认为一旦PINK1进入线粒体，PINK1就会采用拴系的拓扑结构，因为跨膜域和激活域阻止了PINK1向前移动到线粒体中。随后跨膜区下游的蛋白分解释放PINK1进行逆行运动，而PINK1激动域与Hsp90伴侣相互作用。这种双重定位的意义可能意味着PINK1具有特定于脑室的功能。
PINK1 is a mitochondria-targeted kinase that constitutively localizes to both the mitochondria and the cytosol. The mechanism of how PINK1 achieves cytosolic localization following mitochondrial processing remains unknown. Understanding PINK1 subcellular localization will give us insights into PINK1 functions and how mutations in PINK1 lead to Parkinson's disease. We asked how the mitochondrial localization signal, the transmembrane domain, and the kinase domain participate in PINK1 localization. We confirmed that PINK1 mitochondrial targeting signal is responsible for mitochondrial localization. Once inside the mitochondria, we found that both PINK1 transmembrane and kinase domain are important for membrane tethering and cytosolic-facing topology. We also showed that PINK1 dual subcellular distribution requires both Hsp90 interaction with the kinase domain and the proteolysis at a cleavage site downstream of the transmembrane domain because removal of this cleavage site completely abolished cytosolic PINK1. In addition, the disruption of the Hsp90-PINK1 interaction increased mitochondrial PINK1 level. Together, we believe that once PINK1 enters the mitochondria, PINK1 adopts a tethered topology because the transmembrane domain and the kinase domain prevent PINK1 forward movement into the mitochondria. Subsequent proteolysis downstream of the transmembrane domain then releases PINK1 for retrograde movement while PINK1 kinase domain interacts with Hsp90 chaperone. The significance of this dual localization could mean that PINK1 has compartmental-specific functions.
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