Liu Yuhui, Guardia-Laguarta Cristina, Yin Jiang, Erdjument-Bromage Hediye, Martin Brittany, James Michael, Jiang Xuejun, Przedborski Serge
Departments of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA; Center for Motor Neuron Biology and Diseases, Columbia University, New York, NY 10032, USA.
Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
Cell Rep. 2017 Jul 5;20(1):30-39. doi: 10.1016/j.celrep.2017.06.022.
Along with Parkin, PINK1 plays a critical role in maintaining mitochondrial quality control. Although PINK1 is expressed constitutively, its level is kept low in healthy mitochondria by polyubiquitination and ensuing proteasomal degradation of its mature, 52 kDa, form. We show here that the target of PINK1 polyubiquitination is the mature form and is mediated by ubiquitination of a conserved lysine at position 137. Notably, the full-length protein also contains Lys-137 but is not ubiquitinated. On the basis of our data, we propose that cleavage of full-length PINK1 at Phe-104 disrupts the major hydrophobic membrane-spanning domain in the protein, inducing a conformation change in the resultant mature form that exposes Lys-137 to the cytosol for subsequent modification by the ubiquitination machinery. Thus, the balance between the full-length and mature PINK1 allows its levels to be regulated via ubiquitination of the mature form and ensures that PINK1 functions as a mitochondrial quality control factor.
与帕金蛋白（Parkin）一样，PINK1在维持线粒体质量控制方面发挥着关键作用。尽管PINK1是组成性表达，但其水平在健康线粒体中通过多聚泛素化以及随后其成熟的52 kDa形式的蛋白酶体降解而保持在较低水平。我们在此表明，PINK1多聚泛素化的靶标是成熟形式，并且由第137位保守赖氨酸的泛素化介导。值得注意的是，全长蛋白也含有赖氨酸-137，但未被泛素化。基于我们的数据，我们提出全长PINK1在苯丙氨酸-104处的切割破坏了该蛋白中的主要疏水跨膜结构域，诱导了所得成熟形式的构象变化，使赖氨酸-137暴露于胞质溶胶中以便随后被泛素化机制修饰。因此，全长PINK1和成熟PINK1之间的平衡允许通过成熟形式的泛素化来调节其水平，并确保PINK1作为线粒体质量控制因子发挥作用。
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