Characterization of PINK1 (PTEN-induced Putative Kinase 1) Mutations Associated with Parkinson Disease in Mammalian Cells and Drosophila*

Song, Saera; Jang, Seoyeon; Park, Jeehye; Bang, Sunhoe; Choi, Sekyu; Kwon, Kyum‐Yil; Zhuang, Xiaoxi; Kim, Eunjoon; Chung, Jongkyeong

doi:10.1074/jbc.m112.430801

Cited by 67 publications

(46 citation statements)

References 74 publications

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“…4) but failed to undergo complete phosphorylation (Fig. 6) and inhibited Parkin recruitment and activation on depolarized mitochondria (17,47). We thus surmise that the principle functional defect of this mutant is in the process of PINK1 autophosphorylation or substrate recognition.…”

Section: Discussionmentioning

confidence: 97%

“…Constructs harboring the PINK1 KD mutation or one of 10 pathogenic mutations, including C92F, A168P, E240K, H271Q, G309D, L347P, G386A, G409V, E417G, and a pathogenic mutation that results in the insertion of glutamine at amino acid position 534 (referred to hereafter as 534insQ), were generated. These PINK1 mutants, with the exception of C92F, partially or completely impaired phosphorylation and inhibited Parkin recruitment onto depolarized mitochondria without altering mitochondrial localization (16,17,47). HeLa cells expressing PINK1-GFP harboring the aforementioned mutations were subjected to CN-PAGE following CCCP treatment.…”

Section: Development Of a Multicolor Detection Methods To Resolve A Himentioning

confidence: 99%

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A Dimeric PINK1-containing Complex on Depolarized Mitochondria Stimulates Parkin Recruitment

Okatsu

Uno

Koyano

et al. 2013

Journal of Biological Chemistry

196

166

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Background: PINK1 functions on depolarized mitochondria. However, details regarding its mechanism remain limited. Results: We reveal the formation of a high molecular weight complex composed of two phosphorylated PINK1 molecules that stimulates Parkin recruitment. Conclusion:The dimeric PINK1-containing complex is important for mitochondrial quality control. Significance: The PINK1 molecular process is reminiscent of receptor kinase dimerization in signal transduction.

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Section: Discussionmentioning

confidence: 97%

Section: Development Of a Multicolor Detection Methods To Resolve A Himentioning

confidence: 99%

A Dimeric PINK1-containing Complex on Depolarized Mitochondria Stimulates Parkin Recruitment

Okatsu

Uno

Koyano

et al. 2013

Journal of Biological Chemistry

196

166

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“…The UBL Domain Regulates Parkin Translocation to the Mitochondria-Parkin is cytoplasmic but translocates to the mitochondria upon activation by PINK1 (41,43). We sought to determine whether the UBL domain regulates the mitochondrial translocation of Parkin.…”

Section: Resultsmentioning

confidence: 99%

“…The accumulation of PINK1 in the outer membrane triggers recruitment of Parkin to the mitochondria and subsequent ubiquitination of Parkin substrates (38 -42). The ability of PINK1 to recruit Parkin to the mitochondria is absolutely dependent on its kinase activity (41,43). PINK1 phosphorylates Parkin at Ser-65 of the UBL domain (44).…”

mentioning

confidence: 99%

Interaction between RING1 (R1) and the Ubiquitin-like (UBL) Domains Is Critical for the Regulation of Parkin Activity

Ham¹,

Lee

Song

et al. 2016

Journal of Biological Chemistry

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Parkin is an E3 ligase that contains a ubiquitin-like (UBL)domain Parkinson disease (PD)3 is a neurodegenerative disorder that results from degenerated dopaminergic neurons in the substantia nigra. Most cases of PD are sporadic, and ϳ10% are familial (1). Gene mutations that are known to be responsible for the onset of the disease include PARK2 (Parkin), PARK6 (PINK1), PARK7 (DJ-1), LRRK2, and SNCA (␣-synuclein). LRRK2 and SNCA mutations are believed to cause PD through a gain of function, whereas PARK2, PARK6, and PARK7 mutations cause PD through a loss of function (2-4).Autosomal recessive early onset parkinsonism is linked to several loci, including PARK2 and PARK6 (5). The PARK2 gene encodes Parkin, an E3 ubiquitin ligase that consists of 465 amino acid residues. Parkin is composed of an ubiquitin-like (UBL) domain at the N terminus and a R1-in-between-ring (IBR)-Rind 2 (R2) motif at the C terminus (6 -8). Structurally, Parkin is a RING-type E3 ligase, but functionally it acts as a RING/HECT hybrid E3 ligase (9 -12). Parkin functions like a RING-type E3 ligase by interacting with E2 enzymes, UbcH7 and UbcH8, via the IBR domain, whereas the RING1 domain binds to substrates, allowing direct substrate ubiquitination. Parkin can also function like a HECT-type E3 ligase by catalyzing the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to the substrates via the active-site residues, Cys-431 and His-433. E2 enzymes that support Parkin function as a HECT-type E3 ligase are UbcH7, UbcH8, and Ubc13/Uev1a heterodimer (13,14).Substrates that are ubiquitinated by active Parkin include mitofusin (Mfn) 1 and 2, dynamin-related protein 1 (Drp1), voltage-dependent anion-selective channel protein 1 (VDAC1), mitochondrial Rho GTPase (Miro), and translocase of outer membrane 20 (TOM20) (15)(16)(17)(18)(19)(20). Parkin ligates these substrates with [21][22][23]. The substrates of Parkin with Lys-48-linked polyubiquitin chains are degraded by the ubiquitin proteasome system (23-26). However, those polyubiquitinated with Lys-63 or Lys-27 ubiquitin linkage recruit ubiquitin-binding adaptors such as histone deacetylase 6 (HDAC6) and p62/SQSTM1 (21,(27)(28)(29). The stability of Mfn1 and -2 and Drp1 are reduced by 30,31). TOM20 is both mono-and polyubiquitinated by Parkin by . In the case of VDAC1, Parkin catalyzes polyubiquitination with ubiquitin Lys-27 and Lys-63 linkages, which leads to recruitment of p62/SQSTM1 and subsequent induction of mitophagy (18,32).

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“…Upon mitochondrial damage, such as depolarization (Narendra et al, 2008), increased ROS production (Yang and Yang, 2013), activation of the mitochondrial unfolded protein response (mtUPR) (Jin and Youle, 2013) or expression of the short mitochondrial isoform of ARF (smARF, encoded by CDKN2A) (Grenier et al, 2014), PINK1 accumulates on the outer mitochondrial membrane and subsequently recruits the E3 ubiquitin ligase parkin to ubiquitylate outer mitochondrial membrane proteins (Matsuda et al, 2010;Narendra et al, 2010b;Sarraf et al, 2013;Vives-Bauza et al, 2010) (see poster). Parkinson's-disease-associated mutations in PINK1 and parkin disrupt their respective kinase and ubiquitylating activities (Lee et al, 2010a;Song et al, 2013;Sriram et al, 2005), leading to defective mitochondrial degradation. Depletion of DJ-1, another Parkinson's-disease-associated gene, disrupts both mitochondrial dynamics and morphology (Hao et al, 2010;Irrcher et al, 2010;Thomas et al, 2011).…”

Section: Dynamics Of Mitochondrial Degradation In Neurodegenerative Dmentioning

confidence: 99%

Autophagosome dynamics in neurodegeneration at a glance

Wong

Holzbaur

2015

Journal of Cell Science

116

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Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration.

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Characterization of PINK1 (PTEN-induced Putative Kinase 1) Mutations Associated with Parkinson Disease in Mammalian Cells and Drosophila*

Cited by 67 publications

References 74 publications

A Dimeric PINK1-containing Complex on Depolarized Mitochondria Stimulates Parkin Recruitment

A Dimeric PINK1-containing Complex on Depolarized Mitochondria Stimulates Parkin Recruitment

Interaction between RING1 (R1) and the Ubiquitin-like (UBL) Domains Is Critical for the Regulation of Parkin Activity

Autophagosome dynamics in neurodegeneration at a glance

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