PINK1 Kinase Catalytic Activity Is Regulated by Phosphorylation on Serines 228 and 402
PINK1 Kinase Catalytic Activity Is Regulated by Phosphorylation on Serines 228 and 402
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DOI：
10.1074/jbc.m114.620906
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发表时间：
2015-01-30
影响因子：
4.8
通讯作者：
Morais, Vanessa A.
中科院分区：
文献类型：
--
作者：
Aerts, Liesbeth;Craessaerts, Katleen;Morais, Vanessa A.
背景：PINK 1突变影响线粒体稳态并导致帕金森病。结果：PINK 1在线粒体外膜上被磷酸化。我们发现丝氨酸228和402的磷酸化增加了PINK 1磷酸化其底物Parkin和Ubiquitin的能力。结论：PINK 1磷酸化调节其激酶活性。重要性：了解PINK 1的调控是解开其线粒体功能的关键。PINK 1基因突变导致早发性隐性帕金森病。PINK 1是一种神经靶向激酶，调节线粒体生物学的多个方面，从氧化磷酸化到线粒体清除。PINK 1本身也被磷酸化，这可能与其多种活性的调节有关。在这里，我们系统地分析了四个先前确定的磷酸化位点在PINK 1的作用，自磷酸化，底物磷酸化和线粒体自噬。我们的数据表明，这些网站，Ser-228和Ser-402，是自磷酸化截短的PINK 1，但不是全长PINK 1，这表明，N端有抑制作用的磷酸化。我们进一步确定这些PINK 1残基的磷酸化调节底物帕金蛋白和泛素的磷酸化。特别是Ser-402磷酸化似乎对PINK 1功能很重要，因为它参与帕金募集和诱导线粒体自噬。最后，我们确定了Thr-313作为一个残基，这是PINK 1催化活性的关键，但是，与以前的报告相比，我们没有发现证据表明，这种活动是由磷酸化调节。这些数据阐明了PINK 1通过多位点磷酸化的调节。
Background: PINK1 mutations affect mitochondrial homeostasis and cause Parkinson disease. Results: PINK1 is phosphorylated on the outer mitochondrial membrane. We show here that phosphorylation of serines 228 and 402 increases the capacity of PINK1 to phosphorylate its substrates Parkin and Ubiquitin. Conclusion: PINK1 phosphorylation regulates its kinase activity. Significance: Understanding PINK1 regulation is pivotal to unravel its mitochondrial function.Mutations in the PINK1 gene cause early-onset recessive Parkinson disease. PINK1 is a mitochondrially targeted kinase that regulates multiple aspects of mitochondrial biology, from oxidative phosphorylation to mitochondrial clearance. PINK1 itself is also phosphorylated, and this might be linked to the regulation of its multiple activities. Here we systematically analyze four previously identified phosphorylation sites in PINK1 for their role in autophosphorylation, substrate phosphorylation, and mitophagy. Our data indicate that two of these sites, Ser-228 and Ser-402, are autophosphorylated on truncated PINK1 but not on full-length PINK1, suggesting that the N terminus has an inhibitory effect on phosphorylation. We furthermore establish that phosphorylation of these PINK1 residues regulates the phosphorylation of the substrates Parkin and Ubiquitin. Especially Ser-402 phosphorylation appears to be important for PINK1 function because it is involved in Parkin recruitment and the induction of mitophagy. Finally, we identify Thr-313 as a residue that is critical for PINK1 catalytic activity, but, in contrast to previous reports, we find no evidence that this activity is regulated by phosphorylation. These data clarify the regulation of PINK1 through multisite phosphorylation.