PINK1 Kinase Catalytic Activity Is Regulated by Phosphorylation on Serines 228 and 402

Aerts, Liesbeth; Craessaerts, Katleen; Strooper, Bart De; Morais, Vanessa A.

doi:10.1074/jbc.m114.620906

Cited by 99 publications

(109 citation statements)

References 48 publications

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“…Moreover, PINK1 activity itself appears to be controlled by autophosphorylation, with the residues S228, T257, and S402 identified as sites of phosphorylation within PINK1 (Kondapalli et al 2012;Okatsu et al 2012;Aerts et al 2015). These sites are critical for PINK1 function in the mitophagy pathway, as autophosphorylation at S228 and S402 enhances the ability of PINK1 to phosphorylate its substrates, PARKIN and Ub (Aerts et al 2015). In line with these findings, mutation of S228 and S402 to alanine abolishes PINK1 activity, inhibiting the mitochondrial recruitment of PARKIN (Okatsu et al 2012).…”

Section: Activation Of Parkin By Pink1-mediated Phosphorylationsupporting

confidence: 65%

“…Evidence suggests that both PINK1-mediated phosphorylation of PARKIN and PARKIN binding to phospho-Ub activate PARKIN, triggering a feed-forward amplification loop to elicit further rounds of PARKIN-mediated ubiquitination and translocation onto the mitochondria. Moreover, PINK1 activity itself appears to be controlled by autophosphorylation, with the residues S228, T257, and S402 identified as sites of phosphorylation within PINK1 (Kondapalli et al 2012;Okatsu et al 2012;Aerts et al 2015). These sites are critical for PINK1 function in the mitophagy pathway, as autophosphorylation at S228 and S402 enhances the ability of PINK1 to phosphorylate its substrates, PARKIN and Ub (Aerts et al 2015).…”

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confidence: 99%

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The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications

2015

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Two Parkinson's disease (PD)-associated proteins, the mitochondrial kinase PINK1 and the E3-ubiquitin (Ub) ligase PARKIN, are central to mitochondrial quality control. In this pathway, PINK1 accumulates on defective mitochondria, eliciting the translocation of PARKIN from the cytosol to mediate the clearance of damaged mitochondria via autophagy (mitophagy). Throughout the different stages of mitophagy, post-translational modifications (PTMs) are critical for the regulation of PINK1 and PARKIN activity and function. Indeed, activation and recruitment of PARKIN onto damaged mitochondria involves PINK1-mediated phosphorylation of both PARKIN and Ub. Through a stepwise cascade, PARKIN is converted from an autoinhibited enzyme into an active phospho-Ubdependent E3 ligase. Upon activation, PARKIN ubiquitinates itself in concert with many different mitochondrial substrates. The Ub conjugates attached to these substrates can in turn be phosphorylated by PINK1, which triggers further cycles of PARKIN recruitment and activation. This feed-forward amplification loop regulates both PARKIN activity and mitophagy. However, the precise steps and sequence of PTMs in this cascade are only now being uncovered. For instance, the Ub conjugates assembled by PARKIN consist predominantly of noncanonical K6-linked Ub chains. Moreover, these modifications are reversible and can be disassembled by deubiquitinating enzymes (DUBs), including Ub-specific protease 8 (USP8), USP15, and USP30. However, PINK1-mediated phosphorylation of Ub can impede the activity of these DUBs, adding a new layer of complexity to the regulation of PARKINmediated mitophagy by PTMs. It is therefore evident that further insight into how PTMs regulate the PINK1-PARKIN pathway will be critical for our understanding of mitochondrial quality control.Phosphorylation and ubiquitination are two post-translational modifications (PTMs) that often occur together in the regulation of signaling cascades. Examples of pathways regulated by both include the epidermal growth factor (EGF) receptor and NFκB signaling pathways (Karin and Ben-Neriah 2000;Nguyen et al. 2013). Typically, the addition of a phosphate moiety onto a particular residue of a substrate protein regulates the ability of an E3-ubiquitin (Ub) ligase to attach Ub onto lysine residues within a substrate (Lin et al. 2002;Gallagher et al. 2006;Dou et al. 2012). Considering the prominent cross-talk between these PTMs, it is not surprising that they are also implicated in many disease-associated pathways, including cancer and neurodegenerative diseases such as Parkinson's disease (PD). PD is a progressive neurodegenerative disorder that in most cases occurs sporadically. However, the discovery of genes responsible for rare familial cases of PD has shed light on the pathogenesis of the disease. For instance, recessive loss-of-function mutations in the PARK2 and PARK6 genes encode the E3-Ub ligase PARKIN and the mitochondrially targeted kinase PINK1, respectively. These two proteins act together through an intricate int...

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Section: Activation Of Parkin By Pink1-mediated Phosphorylationsupporting

confidence: 65%

mentioning

confidence: 99%

The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications

2015

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“…Under physiological conditions, PINK1 protein is imported into the inner mitochondrial membrane (Jin et al , 2010; Shi et al , 2011; Yamano and Youle, 2013). Mitochondrial damage directs PINK1 to the outer mitochondrial membrane, where it rapidly accumulates, is auto-phosphorylated (Okatsu et al , 2012; Aerts et al , 2015) and dimerizes into a supermolecular protein complex (Liu et al , 2009; Okatsu et al , 2013). This activates PINK1's kinase activity, and activated PINK1 then phosphorylates ubiquitin (Kane et al , 2014; Kazlauskaite et al , 2014; Koyano et al , 2014; Shiba-Fukushima et al , 2014) and parkin (Kondapalli et al , 2012; Shiba-Fukushima et al , 2012) at a conserved residue (Ser65).…”

Section: Introductionmentioning

confidence: 99%

Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism

Puschmann

Fiesel

Caulfield

et al. 2016

Brain

121

103

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See Gandhi and Plun-Favreau (doi:) for a scientific commentary on this article.Heterozygous mutations in recessive Parkinson’s disease genes have been postulated to increase disease risk. Puschmann et al. report a genetic association between heterozygous PINK1 p.G411S and Parkinson’s disease. They provide structural and functional explanations for a partial dominant-negative effect of the mutant protein, which impairs wild-type PINK1 activity through hetero-dimerization.

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“…TOMM7, a tail-anchored TOM component, is also required for PINK1-TOM association (but not for PINK1 import and processing) [22]. In this 850 kDa supercomplex, PINK1 homodimerizes and autophosphorylates (at S228 and S402) to become a highly active kinase capable of promoting Parkin translocation to mitochondria [21,23,59].…”

Section: Addresses Introductionmentioning

confidence: 99%

PINK1/Parkin-mediated mitophagy in mammalian cells

Eiyama¹,

Okamoto²

2015

Current Opinion in Cell Biology

418

310

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PINK1 Kinase Catalytic Activity Is Regulated by Phosphorylation on Serines 228 and 402

Cited by 99 publications

References 48 publications

The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications

The three ‘P’s of mitophagy: PARKIN, PINK1, and post-translational modifications

Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism

PINK1/Parkin-mediated mitophagy in mammalian cells

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