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

Okatsu, Kei; Uno, Midori; Koyano, Fumika; Go, Etsu; Kimura, Mayumi; Oka, Toshihiko; Tanaka, Keiji; Matsuda, Noriyuki

doi:10.1074/jbc.m113.509653

Cited by 197 publications

(192 citation statements)

References 61 publications

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“…HeLa cells stably expressing GFP-Parkin (57) were cultured in advanced DMEM (Invitrogen) with 10% fetal bovine serum (Invitrogen), 5 g/ml puromycin (Invitrogen), 200 mM L-glutamine (Invitrogen) at 37°C in a humidified atmosphere of 5% CO 2 . Expression plasmids were transfected using Lipofectamine Plus Reagent (Invitrogen) or polyethyleneimine (Sigma) according to the manufacturer's instructions.…”

Section: Methodsmentioning

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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Section: Methodsmentioning

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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“…When PINK1 accumulates on the outer membrane of depolarized mitochondria, it recruits Parkin from the cytosol. However, previous reports indicate that, besides PINK1 accumulation, PINK1 also needs to be activated by phosphorylation (20,27,28). Therefore, we decided to investigate the implication of each of the four putative phosphosites in Parkin recruitment.…”

Section: P32: Pink1)mentioning

confidence: 99%

“…Different residues have been identified as autophosphorylation sites after CCCP-induced mitochondrial membrane depolarization, namely Ser-228, Thr-257, and Ser-402 (20,27). Two residues, Ser-228 and Ser-402, appear to be involved in PINK1 dimerization and Parkin recruitment (27,28). A fourth putative phosphorylation site in PINK1 is Thr-313, a residue that is regulated by the activity of microtubule affinity regulating kinase 2 (MARK2) (29,30).…”

mentioning

confidence: 99%

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

Aerts

Craessaerts

Strooper

et al. 2015

Journal of Biological Chemistry

104

105

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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.

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“…In this regard, it is important to mention that PINK1 WT interacted with the mitochondrial import central channel TOM40 specifically upon CCCP treatment, but both of the mutations that had reduced HSP90/CDC37 binding, failed. It is known that upon mitochondrial depolarization PINK1 auto-phosphorylates 53) 61) and dimerizes into a higher molecular weight protein complex together with the TOM machinery in the OMM 10) 12) 62) . However, how PINK1 keep stabilization on OMM remained unsolved.…”

Section: Discussionmentioning

confidence: 99%

“…accumulates into a higher molecular weight protein complex with the import machinery 10) 53) , which regulates its insertion into the OMM, stability and enzymatic function towards PARKIN activation. In line with this, PINK1-V5 WT was found to interact with TOM40 specifically upon CCCP treatment, while the PINK1 mutations p. I368N or p. L347P failed, despite comparable amounts of immunoprecipitated PINK1-V5.…”

Section: Full-length Pink1 Pi368n Is Not Stabilized Onmentioning

confidence: 99%

The PINK1 p.I368N Mutation Affects Protein Stability and Kinase Activity with Its Structural Change

Ando

Fiesel

Hudec

et al. 2018

Juntendo Medical Journal

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

Cited by 197 publications

References 61 publications

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

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

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

The PINK1 p.I368N Mutation Affects Protein Stability and Kinase Activity with Its Structural Change

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