Affinage

PRKN

E3 ubiquitin-protein ligase parkin · UniProt O60260

Length
465 aa
Mass
51.6 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRKN encodes Parkin, an RBR-type E3 ubiquitin-protein ligase that is the principal effector of PINK1-directed mitophagy and a cause of autosomal recessive juvenile parkinsonism when mutationally inactivated (PMID:11692161, PMID:19029340). Parkin is normally autoinhibited in the cytosol; upon mitochondrial depolarization, PINK1 accumulates on the outer mitochondrial membrane and phosphorylates ubiquitin at Ser65, which binds a conserved pocket in Parkin's RING1 domain, displacing the Ubl domain and triggering sequential release of the catalytic RING2 domain to expose the active-site cysteine (PMID:24784582, PMID:26161729, PMID:29995846). Activated Parkin ubiquitinates outer mitochondrial membrane substrates including Mfn2, VDAC1, and Miro, building phospho-ubiquitin chains that recruit additional Parkin (feed-forward amplification) and autophagy adaptors to drive autophagosome assembly around damaged mitochondria; failure of this pathway leads to cytosolic mtDNA release and STING-dependent neuroinflammation, linking Parkin loss to dopaminergic neurodegeneration (PMID:25847540, PMID:32047033, PMID:27679849, PMID:30135585). Beyond mitophagy, Parkin ubiquitinates diverse substrates including BCL-XL, β-catenin, EGFR, and PKM2, contributing to apoptosis regulation, cell-cycle control, and metabolic homeostasis (PMID:28038320, PMID:25877876, PMID:26975375).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2001 High

    Establishing that Parkin is an E3 ubiquitin-protein ligase—and that loss of this activity underlies autosomal recessive juvenile parkinsonism—converted a genetically mapped disease locus into a defined enzymatic function.

    Evidence In vitro ubiquitin ligase reconstitution with E2 specificity profiling and pathogenic mutation analysis

    PMID:11692161

    Open questions at the time
    • Physiological substrates unknown
    • Mechanism of autoinhibition not yet defined
    • No structural information
  2. 2008 High

    Discovery that Parkin selectively translocates to depolarized mitochondria and promotes their autophagic clearance established mitophagy as Parkin's central cellular function, while genetic epistasis in Drosophila placed PINK1/Parkin upstream of mitochondrial fission/fusion dynamics.

    Evidence Live-cell imaging and membrane-potential assays in mammalian cells; Drosophila double-mutant analysis with drp1, Opa1, Mfn2

    PMID:18230723 PMID:19029340

    Open questions at the time
    • Upstream signal triggering Parkin recruitment unknown
    • Mechanism linking Parkin to fission machinery unclear
    • Identity of mitochondrial ubiquitin substrates not yet determined
  3. 2010 High

    Demonstrating that PINK1 accumulation on damaged mitochondria is both necessary and sufficient for Parkin recruitment established the PINK1→Parkin epistatic axis and explained how mitochondrial damage is sensed.

    Evidence Genetic epistasis with PINK1 overexpression/knockdown, disease mutations, and mitophagy assays in mammalian cells

    PMID:20126261

    Open questions at the time
    • Biochemical mechanism of PINK1-mediated Parkin activation (phosphorylation target) unknown
    • Whether PINK1 directly phosphorylates Parkin or acts indirectly unresolved
  4. 2014 High

    Identification of Ser65-phosphorylated ubiquitin as a PINK1 product and allosteric Parkin activator revealed the dual-key activation mechanism (phospho-Ubl + phospho-ubiquitin) and explained how Parkin's latent E3 activity is unleashed on mitochondria.

    Evidence In vitro kinase assays, phosphopeptide mass spectrometry, ubiquitin-discharge assays with recombinant proteins; Drosophila phosphomimetic Parkin in vivo

    PMID:24784582 PMID:24901221

    Open questions at the time
    • Structural basis for phospho-ubiquitin binding to Parkin undetermined
    • Full domain rearrangement upon activation not yet visualized
  5. 2015 High

    Crystal structures of Parkin–phospho-ubiquitin complexes, combined with the demonstration that phospho-ubiquitin chains serve as the mitochondrial Parkin receptor, defined the feed-forward amplification loop: Parkin builds ubiquitin chains → PINK1 phosphorylates them → phospho-Ub chains recruit more Parkin.

    Evidence X-ray crystallography (Pediculus Parkin–pUb complex), SAXS, cellular ubiquitin-replacement system, in vitro reconstitution with phosphomimetic tetra-ubiquitin

    PMID:25847540 PMID:26161729 PMID:26254305

    Open questions at the time
    • Structure of fully activated human Parkin not yet solved
    • Catalytic RING2 domain release not structurally visualized
    • Relative contributions of different OMM substrates to amplification loop unclear
  6. 2018 High

    High-resolution structures of phosphorylated human Parkin and insect Parkin–E2 complexes revealed the complete two-step activation mechanism: phospho-Ubl rebinds to UPD via a disease-mutation-lined pocket, releasing RING2 and the ACT linker, exposing the catalytic cysteine.

    Evidence 1.8 Å crystal structure of phosphorylated human Parkin, HDX-MS, NMR of activation intermediates, crystal structure of phosphorylated Bactrocera Parkin–pUb–E2 complex

    PMID:29967542 PMID:29995846

    Open questions at the time
    • No structure of Parkin engaged with a mitochondrial substrate
    • Dynamics of membrane-proximal activation not captured
  7. 2015 Medium

    Identification of deubiquitinases USP8, USP30, and USP35 as regulators that oppose Parkin autoubiquitination and substrate ubiquitination established that mitophagy is tuned by an antagonistic DUB network, not solely by PINK1-Parkin activation.

    Evidence Ubiquitin-linkage analysis, USP knockdown/overexpression, quantitative mitophagy assays

    PMID:25700639 PMID:25915564

    Open questions at the time
    • Relative physiological importance of each DUB in neurons undetermined
    • Structural basis for K6-linkage selectivity of USP8 on Parkin unknown
    • In vivo validation in mammalian models lacking
  8. 2016 High

    Demonstration that Parkin-dependent ubiquitination of Miro arrests axonal mitochondrial transport and that RABGEF1 recruitment to ubiquitinated mitochondria activates endosomal Rab cascades for ATG9A vesicle assembly connected Parkin's E3 activity to both mitochondrial motility arrest and autophagosome nucleation.

    Evidence Phosphomimetic Miro mutagenesis with axonal transport imaging; siRNA of RABGEF1/RAB7A with ATG9A vesicle assembly assays

    PMID:27679849 PMID:29360040

    Open questions at the time
    • Whether Miro phosphorylation by PINK1 is the obligate trigger for Parkin-Miro interaction in all cell types is unclear
    • How ATG9A vesicles transition to LC3-positive autophagosomes at the mitochondrial surface not mechanistically resolved
  9. 2018 High

    Linking PINK1/Parkin-mediated mitophagy to suppression of STING-dependent innate immunity provided a direct pathogenic mechanism for neurodegeneration: in the absence of Parkin, cytosolic mtDNA accumulates and triggers neuroinflammation, which is rescued by STING deletion.

    Evidence Prkn−/−, Pink1−/−, and Prkn−/−;STING−/− knockout mice with exhaustive exercise and mutator backgrounds; cytokine measurements, dopaminergic neuron counts

    PMID:30135585

    Open questions at the time
    • Whether STING-mediated inflammation is the primary driver of dopaminergic neuron loss in human PD is not established
    • Contribution of other innate immune sensors (cGAS, TLR9) to Parkin-loss phenotypes not delineated
  10. 2020 High

    Dissection of VDAC1 mono- versus polyubiquitination by Parkin separated mitophagy (polyubiquitination-dependent) from anti-apoptotic signaling (monoubiquitination at K274 suppresses MCU-mediated Ca²⁺ uptake), revealing that Parkin has ubiquitin-chain-type-specific, functionally distinct outputs on a single substrate.

    Evidence Ubiquitination site mutagenesis, mitophagy and apoptosis assays, mitochondrial calcium measurements, Drosophila transgenic rescue with PD-patient Parkin T415N mutant

    PMID:32047033

    Open questions at the time
    • Whether this mono/polyUb distinction applies to other Parkin substrates untested
    • E2 enzyme(s) specifying chain type on VDAC1 not identified
  11. 2024 High

    Massively parallel functional profiling of ~9,200 Parkin variants mapped a degron near the ACT element and showed that most pathogenic missense variants cause protein instability and proteasomal degradation, unifying the genotype-phenotype landscape.

    Evidence VAMP-seq in human cells with proteasome inhibitor rescue and structural degron mapping

    PMID:38378758

    Open questions at the time
    • Variant effects on enzymatic activity and mitophagy not measured in parallel
    • Whether degradation-prone variants can be pharmacologically stabilized in neurons is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for Parkin engagement with mitochondrial-membrane-embedded substrates, the relative contribution of individual substrates to mitophagy versus non-mitophagy functions in dopaminergic neurons, and whether pharmacological Parkin activation can be achieved therapeutically.
  • No structure of membrane-engaged Parkin ubiquitinating a substrate
  • Substrate hierarchy on damaged mitochondria not systematically defined in neurons
  • No pharmacological Parkin activator validated in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016874 ligase activity 3
Localization
GO:0005739 mitochondrion 6 GO:0005829 cytosol 2
Pathway
R-HSA-9612973 Autophagy 6 R-HSA-392499 Metabolism of proteins 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-168256 Immune System 1
Partners
MFN2PINK1RHOT1RHOT2USP30USP33VDAC1VPS35

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 Parkin is selectively recruited from the cytosol to dysfunctional mitochondria with low membrane potential, where it mediates engulfment of mitochondria by autophagosomes and promotes selective elimination of impaired mitochondria (mitophagy). Live-cell imaging, mitochondrial membrane potential assays, autophagosome colocalization in mammalian cells The Journal of cell biology High 19029340
2010 PINK1 accumulation on damaged mitochondria (regulated by voltage-dependent proteolysis that keeps PINK1 low on healthy mitochondria) is both necessary and sufficient for Parkin recruitment to mitochondria; disease-causing mutations in PINK1 and Parkin disrupt Parkin recruitment and Parkin-induced mitophagy at distinct steps, establishing PINK1 acts upstream of Parkin. Genetic epistasis in mammalian cells, dominant-negative and loss-of-function mutations, PINK1 overexpression/knockdown, mitophagy assays PLoS biology High 20126261
2014 PINK1 phosphorylates ubiquitin at Ser65 both in vitro and in cells; phosphorylated ubiquitin (phosphoUb) acts as an allosteric activator of Parkin E3 ligase activity by accelerating discharge of the UbcH7~ubiquitin thioester conjugate; PINK1-dependent phosphorylation of both Parkin and ubiquitin is sufficient for full activation of Parkin E3 activity. In vitro kinase assay, phosphopeptide mass spectrometry, in vitro ubiquitin discharge assay with recombinant proteins, phosphomimetic ubiquitin rescue experiments in cells Nature High 24784582
2015 Crystal structure of Pediculus humanus Parkin in complex with Ser65-phosphorylated ubiquitin reveals the molecular basis for Parkin recruitment and activation: phosphoUb binds a conserved phosphate pocket in RING1 (involving AR-JP mutation residues), straightens a RING1 helix causing conformational changes that release the Ubl domain from the Parkin core, activating Parkin; phosphoUb-mediated Ubl release also enhances Ubl phosphorylation by PINK1, stabilizing an open active conformation. Crystal structure (X-ray crystallography), mutagenesis, biochemical binding assays Nature High 26161729
2018 Full-length human Parkin undergoes large-scale domain rearrangement upon activation: phospho-Ubl rebinds to the Parkin core (UPD domain via a phosphate-binding pocket lined by AR-JP mutations) and releases the catalytic RING2 domain; a conserved linker region (ACT element) between Ubl and UPD mimics RING2 interactions to aid RING2 release; 1.8 Å crystal structure of phosphorylated human Parkin determined. Hydrogen-deuterium exchange mass spectrometry, 1.8 Å crystal structure of phosphorylated human Parkin, mutagenesis Nature High 29995846
2018 Crystal structure of phosphorylated Bactrocera dorsalis Parkin in complex with phosphorylated ubiquitin and an E2 ubiquitin-conjugating enzyme reveals that the key activating step is movement of the Ubl domain and release of the catalytic RING2 domain; HDX and NMR experiments with activation intermediates confirm large domain movements in mammalian Parkin activation. Crystal structure (X-ray crystallography), hydrogen/deuterium exchange, NMR, mutagenesis Nature structural & molecular biology High 29967542
2015 Phosphorylated ubiquitin chain (not monomeric phosphoUb) is the genuine Parkin receptor on mitochondria: linear phosphomimetic tetra-ubiquitin(S65D) recruits Parkin to energized mitochondria in absence of PINK1; physical interaction between phosphomimetic Parkin and phosphorylated polyubiquitin chain detected by Co-IP from cells and by in vitro reconstitution with recombinant proteins. Cellular ubiquitin replacement system, Co-IP from cells, in vitro reconstitution with recombinant proteins, lysosomal phosphorylated polyubiquitin chain recruitment assay The Journal of cell biology High 25847540
2015 Phospho-ubiquitin binding to RING1 of Parkin (at His302/Arg305) promotes disengagement of the Ubl domain from RING1 and subsequent Parkin phosphorylation by PINK1; mutations mimicking pUb binding (releasing Ubl from RING1) promote Parkin phosphorylation and E3 ligase activity; SAXS and crystal structure at 2.54 Å of Parkin Δ86-130 used to define the binding switch. Mutagenesis, SAXS, 2.54 Å crystal structure, E2 (UbcH7) binding assays, E3 ligase activity assay The EMBO journal High 26254305
2008 In Drosophila, the PINK1/Parkin pathway promotes mitochondrial fission: heterozygous loss of drp1 is largely lethal in PINK1 or parkin mutant background; flight muscle degeneration and mitochondrial morphology defects of PINK1/parkin mutants are suppressed by increased drp1 dosage and by heterozygous loss of fusion factors OPA1 and Mfn2, establishing PINK1/Parkin promote fission and that loss of fission underlies mutant phenotypes. Drosophila genetic epistasis, double-mutant analysis, mitochondrial morphology quantification Proceedings of the National Academy of Sciences of the United States of America High 18230723
2018 Parkin and PINK1 suppress STING-mediated inflammatory signaling: Prkn-/- and Pink1-/- mice develop strong inflammation following exhaustive exercise or mtDNA mutation accumulation; inflammation and dopaminergic neuron loss are rescued by concurrent STING loss, demonstrating PINK1/Parkin-mediated mitophagy restrains innate immunity by limiting cytosolic mtDNA-triggered STING activation. Knockout mouse models (Prkn-/-, Pink1-/-, Prkn-/-;STING-/-, Prkn-/-;mutator mice), cytokine measurements, dopaminergic neuron counts, genetic rescue Nature High 30135585
2016 RABGEF1, an upstream factor of the endosomal Rab GTPase cascade, is recruited to damaged mitochondria via ubiquitin binding downstream of Parkin; RABGEF1 directs RAB5 and RAB7A to damaged mitochondria; RAB7A depletion inhibits ATG9A vesicle assembly and subsequent autophagosome encapsulation of mitochondria, revealing that Parkin-dependent endosomal Rab cycles regulate mitophagy by assembling ATG9A vesicles. siRNA knockdown, co-immunoprecipitation, live-cell imaging, ATG9A vesicle assembly assay in mammalian cells eLife High 29360040
2016 PINK1 phosphorylation of Miro on S156 promotes Parkin interaction with Miro, Miro ubiquitination and degradation, Parkin recruitment to mitochondria, and Parkin-dependent arrest of axonal mitochondrial transport; phosphomimetic Miro T298E/T299E inhibits PINK1-induced Miro ubiquitination, Parkin recruitment, and mitochondrial arrest. Phosphomimetic and non-phosphorylatable Miro mutants, co-immunoprecipitation, axonal transport imaging in neurons Proceedings of the National Academy of Sciences of the United States of America High 27679849
2020 Parkin mediates both mono- and polyubiquitination of VDAC1 in a PINK1-dependent manner; VDAC1 polyubiquitination is required for mitophagy whereas VDAC1 monoubiquitination (K274) suppresses apoptosis by limiting mitochondrial calcium uptake through the MCU channel; a PD patient Parkin mutation T415N loses monoubiquitination but retains polyubiquitination capacity and fails to rescue PD phenotypes in Drosophila. Ubiquitination site mutagenesis, Drosophila transgenic models, mitophagy assays, apoptosis assays, mitochondrial calcium measurements Proceedings of the National Academy of Sciences of the United States of America High 32047033
2010 Parkin directly binds Bcl-2 via its C terminus and mediates mono-ubiquitination of Bcl-2, increasing Bcl-2 steady-state levels and enhancing Bcl-2/Beclin-1 interaction to inhibit autophagy; overexpression of E3 ligase-deficient Parkin does not affect LC3 conversion, establishing E3 activity is required. Co-immunoprecipitation, in vitro ubiquitination assay, LC3 conversion assay, Parkin knockdown/overexpression The Journal of biological chemistry Medium 20889974
2015 Parkin interacts with APC/C coactivators Cdc20 and Cdh1 to mediate degradation of key mitotic regulators independently of APC/C; Parkin is phosphorylated and activated by Polo-like kinase 1 (Plk1) during mitosis; Parkin deficiency causes mitotic defects, genomic instability, and overexpression of mitotic substrates. Co-immunoprecipitation, in vitro ubiquitination assay, kinase assay (Plk1 phosphorylation of Parkin), Parkin knockout cell mitosis assays Molecular cell Medium 26387737
2016 Parkin interacts with pyruvate kinase M2 (PKM2) both in vitro and in vivo; this interaction is increased during glucose starvation; Parkin ubiquitinates PKM2 without affecting its stability but decreases its enzymatic activity, thereby regulating glycolysis. Biochemical purification, co-immunoprecipitation, in vitro ubiquitination assay, PKM2 enzymatic activity assay The Journal of biological chemistry Medium 26975375
2018 Parkin ubiquitinates Mfn2, and Parkin-dependent ubiquitination of Mfn2 regulates ER-mitochondria tethering; Parkin-deficient cells and parkin-mutant human fibroblasts show decreased ER-mitochondria contact; a non-ubiquitinatable Mfn2 mutant fails to restore ER-mitochondria physical and functional interaction; catalytically inactive Parkin has no effect on cytosolic Ca2+ transients. Confocal microscopy (ER-mitochondria contact quantification), Ca2+ flux measurements, Parkin KO mouse fibroblasts, patient fibroblasts, Mfn2 ubiquitination site mutagenesis, Drosophila in vivo locomotion rescue Pharmacological research Medium 30219582
2018 Parkin mediates ubiquitination of VPS35 (retromer component) with atypical poly-ubiquitin chains at three C-terminal lysines; this ubiquitination does not promote proteasomal degradation of VPS35 but parkin knockout mice show marked decrease in WASH complex components and selective disruption of ATG9A vesicular sorting, suggesting Parkin modulates retromer-dependent endosomal sorting. Co-immunoprecipitation, in vitro ubiquitination assay, ubiquitin chain linkage analysis, parkin KO mouse brain fractionation, ATG9A trafficking assay in primary cortical neurons Human molecular genetics Medium 29893854
2015 USP8 deubiquitinase preferentially removes K6-linked ubiquitin conjugates from Parkin autoubiquitination; USP8 silencing causes persistence of K6-linked Ub conjugates on Parkin, delaying its translocation to damaged mitochondria and completion of mitophagy. Co-immunoprecipitation, ubiquitin linkage analysis, USP8 knockdown, quantitative mitophagy assay Autophagy Medium 25700639
2019 USP33 localizes to the outer mitochondrial membrane, interacts with Parkin, and deubiquitinates Parkin in a DUB activity-dependent manner, preferentially removing K6, K11, K48, and K63-linked ubiquitin conjugates mainly at Lys435; USP33 knockdown increases Parkin protein stability and translocation to depolarized mitochondria, enhancing mitophagy. Co-immunoprecipitation, in vitro deubiquitination assay, ubiquitin linkage-specific analysis, Parkin translocation assay, quantitative mitophagy assay Autophagy Medium 31432739
2015 Deubiquitinating enzymes USP30 and USP35 regulate Parkin-mediated mitophagy; USP30 delays mitophagy by delaying Parkin recruitment to mitochondria; USP35 regulates mitophagy through an alternative mechanism and translocates from mitochondria to cytosol during CCCP-induced mitophagy. Quantitative mitophagy assay, USP overexpression/knockdown, Parkin recruitment assay by live imaging Autophagy Medium 25915564
2021 MITOL/MARCH5 ubiquitinates Parkin at lysine 220 to promote its proteasomal degradation; MITOL-mediated Parkin degradation fine-tunes mitophagy by controlling Parkin quantity; MITOL deletion leads to accumulation of phosphorylated active Parkin in the ER, causing FKBP38 degradation and enhanced cell death. Co-immunoprecipitation, in vitro ubiquitination assay, ubiquitination site mutagenesis (K220), proteasome inhibitor experiments, MITOL deletion cellular assays EMBO reports Medium 33565245
2012 Parkin and PINK1 are subject to neddylation (NEDD8 conjugation); neddylation of Parkin increases its E3 ligase activity; PD neurotoxin MPP+ inhibits neddylation of both Parkin and PINK1. In vitro neddylation assay, E3 ligase activity assay, Drosophila dAPP-BP1 overexpression epistasis, MPP+ treatment experiments Human molecular genetics Medium 22388932
2008 Combined phosphorylation of Parkin by casein kinase I and cyclin-dependent kinase 5 (Cdk5) decreases Parkin solubility, causing its aggregation and inactivation; combined kinase inhibition partially reverses aggregative properties of pathogenic Parkin point mutants; enhanced Parkin phosphorylation is detected in brain areas of sporadic PD patients and correlates with increased p25 (Cdk5 activator) levels. In vitro kinase assay, Parkin solubility/aggregation assay, kinase inhibitor treatment in cells, sporadic PD brain tissue analysis Human molecular genetics Medium 19050041
2019 PHB2 stabilizes PINK1 on mitochondria via the PARL-PGAM5-PINK1 axis; PHB2 depletion destabilizes PINK1, blocking PRKN/Parkin recruitment to mitochondria; PHB2 overexpression directly induces Parkin recruitment; PHB2-mediated mitophagy is dependent on the inner membrane protease PARL and on PGAM5 processing by PARL. PHB2 knockdown/overexpression, PINK1 stability assay, Parkin translocation assay, PARL and PGAM5 genetic manipulation in mouse embryo fibroblasts Autophagy Medium 31177901
2018 Miro1 interacts with a small pool of Parkin before mitochondrial damage in a PINK1-independent and ubiquitination-independent manner, serving as a calcium-sensitive docking site for Parkin on mitochondria; knockdown of Miro proteins reduces Parkin translocation to mitochondria and suppresses mitophagy; Miro1 EF-hand domains control Miro1 ubiquitination and Parkin recruitment. Co-immunoprecipitation, Miro knockdown, live-cell Parkin translocation assay, EF-hand domain mutagenesis The EMBO journal Medium 30504269
2001 Parkin functions as a RING-type E3 ubiquitin-protein ligase collaborating with E2 ubiquitin-conjugating enzymes UbcH7 and UbcH8; loss of this E3 ligase activity is the molecular basis of autosomal recessive juvenile parkinsonism. In vitro ubiquitin ligase assay, E2 enzyme specificity assay, pathogenic mutation functional analysis Journal of molecular medicine (Berlin, Germany) High 11692161
2009 Parkin promotes DNA repair: parkin-deficient cells show reduced DNA excision repair restored by wild-type but not pathological mutant Parkin; Parkin interacts with PCNA (proliferating cell nuclear antigen), a coordinator of DNA excision repair; Parkin protects against DNA damage-induced cell death. DNA repair assay in parkin-deficient cells, transfection rescue with WT vs. mutant Parkin, co-immunoprecipitation with PCNA, cell death assay Biochemical and biophysical research communications Low 19285961
2015 PARK2 physically interacts with β-catenin and EGFR and promotes their ubiquitination in an E3 ligase activity-dependent manner, downregulating Wnt- and EGF-stimulated pathways and inhibiting glioma cell growth. Co-immunoprecipitation, in vitro/cellular ubiquitination assay, PARK2 overexpression/knockdown in glioma cells, in vivo xenograft Cancer research Medium 25877876
2016 PARK2 directly binds to and ubiquitinates BCL-XL; PARK2 inactivation leads to aberrant accumulation of BCL-XL in vitro and in vivo; cancer-specific PARK2 mutations abrogate ubiquitination of BCL-XL; PARK2 modulates mitochondrial depolarization and apoptosis in a BCL-XL-dependent manner. Co-immunoprecipitation, in vitro ubiquitination assay, PARK2 KO mouse tissue, functional apoptosis assay Neoplasia (New York, N.Y.) Medium 28038320
2014 In Drosophila, PINK1-mediated phosphorylation of Parkin at Ser94 (equivalent to human Ser65) boosts Parkin ubiquitin-ligase activity; phosphomimetic Parkin accelerates mitochondrial fragmentation/aggregation and mitochondrial protein degradation independently of PINK1 activity; non-phosphorylatable Parkin cannot rescue PINK1-null muscle phenotype fully; Parkin phosphorylation affects dopamine release and dopaminergic neuron survival in vivo. Drosophila transgenic models expressing phosphomimetic and non-phosphorylatable Parkin, mitochondrial morphology assay, dopamine release measurement, dopaminergic neuron survival quantification PLoS genetics Medium 24901221
2023 PRKN/Parkin ubiquitinates PA2G4/EBP1 at lysine 376 on damaged mitochondria; ubiquitinated PA2G4/EBP1 interacts with autophagy receptor SQSTM1/p62 to induce mitophagy; neuron-specific Pa2g4 knockout impairs mitophagy and worsens ischemia-reperfusion neuronal death. Ubiquitination site mutagenesis, co-immunoprecipitation, neuron-specific knockout mouse, ischemia-reperfusion model, AAV rescue Autophagy Medium 37712850
2023 Under hypoxia, GPCPD1 (depalmitoylated by LYPLA1) relocates to the outer mitochondrial membrane and binds VDAC1, disrupting VDAC1 oligomerization; increased VDAC1 monomer provides more sites for PRKN-mediated polyubiquitination, triggering mitophagy. Co-immunoprecipitation, VDAC1 oligomerization assay, PRKN ubiquitination assay, GPCPD1 depalmitoylation assay, mitophagy quantification Autophagy Low 36803235
2024 Massively parallel variant abundance by sequencing (VAMP-seq) of 9219 Parkin variants in human cells shows most low-abundance variants are proteasome targets located in structured domains; a degron region proximal to the activation element (ACT) is mapped; missense variants cause degradation either by destabilizing the native protein or by introducing local degradation signals. VAMP-seq (variant abundance by massively parallel sequencing), proteasome inhibitor experiments, structural mapping of degrons Nature communications High 38378758

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. The Journal of cell biology 3295 19029340
2010 PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS biology 2377 20126261
2014 Ubiquitin is phosphorylated by PINK1 to activate parkin. Nature 1199 24784582
2018 Parkin and PINK1 mitigate STING-induced inflammation. Nature 1057 30135585
2008 The PINK1/Parkin pathway regulates mitochondrial morphology. Proceedings of the National Academy of Sciences of the United States of America 710 18230723
2015 Mechanism of phospho-ubiquitin-induced PARKIN activation. Nature 388 26161729
2020 PINK1/PARKIN signalling in neurodegeneration and neuroinflammation. Acta neuropathologica communications 368 33168089
2019 PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy 334 31177901
2018 Mechanism of parkin activation by PINK1. Nature 306 29995846
2011 Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxidants & redox signaling 294 21194381
2017 PINK1 and Parkin: emerging themes in mitochondrial homeostasis. Current opinion in cell biology 269 28437683
2016 Mechanisms of mitophagy: PINK1, Parkin, USP30 and beyond. Free radical biology & medicine 261 27094585
2018 PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury. Autophagy 253 29172924
2016 Parkin and mitophagy in cancer. Oncogene 231 27593930
2015 Phosphorylated ubiquitin chain is the genuine Parkin receptor. The Journal of cell biology 225 25847540
2018 PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism. Developmental cell 221 30100261
2021 Regulation of PRKN-independent mitophagy. Autophagy 199 33570005
2015 Parkin structure and function. The FEBS journal 190 25712550
2018 PRKN-regulated mitophagy and cellular senescence during COPD pathogenesis. Autophagy 187 30290714
2018 No Parkin Zone: Mitophagy without Parkin. Trends in cell biology 186 30115557
2015 Deubiquitinating enzymes regulate PARK2-mediated mitophagy. Autophagy 185 25915564
2020 Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination. Proceedings of the National Academy of Sciences of the United States of America 183 32047033
2018 Regulation of ER-mitochondria contacts by Parkin via Mfn2. Pharmacological research 179 30219582
2015 A Ubl/ubiquitin switch in the activation of Parkin. The EMBO journal 166 26254305
2011 Regulation of PINK1-Parkin-mediated mitophagy. Autophagy 153 21187721
2018 Mechanism of parkin activation by phosphorylation. Nature structural & molecular biology 144 29967542
2020 The PINK1/PARK2/optineurin pathway of mitophagy is activated for protection in septic acute kidney injury. Redox biology 143 33137712
2019 SQSTM1/p62 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin in mitophagy. Autophagy 142 31339428
2010 Parkin mono-ubiquitinates Bcl-2 and regulates autophagy. The Journal of biological chemistry 142 20889974
2021 Newcastle disease virus degrades SIRT3 via PINK1-PRKN-dependent mitophagy to reprogram energy metabolism in infected cells. Autophagy 141 34720029
2020 Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism. Brain : a journal of neurology 139 33029617
2018 Endosomal Rab cycles regulate Parkin-mediated mitophagy. eLife 138 29360040
2016 Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility. Proceedings of the National Academy of Sciences of the United States of America 132 27679849
2014 Functional interplay between Parkin and Drp1 in mitochondrial fission and clearance. Biochimica et biophysica acta 131 24878071
2016 The endoplasmic reticulum-mitochondria interface is perturbed in PARK2 knockout mice and patients with PARK2 mutations. Human molecular genetics 125 27206984
2016 Parkin and PINK1 functions in oxidative stress and neurodegeneration. Brain research bulletin 122 28017782
2020 The PINK1-Parkin axis: An Overview. Neuroscience research 112 31982458
2018 Miro proteins prime mitochondria for Parkin translocation and mitophagy. The EMBO journal 110 30504269
2019 USP33 deubiquitinates PRKN/parkin and antagonizes its role in mitophagy. Autophagy 108 31432739
2019 Drp1-regulated PARK2-dependent mitophagy protects against renal fibrosis in unilateral ureteral obstruction. Free radical biology & medicine 101 31825802
2015 Temporal dynamics of PARK2/parkin and OPTN/optineurin recruitment during the mitophagy of damaged mitochondria. Autophagy 98 25801386
2004 How does parkin ligate ubiquitin to Parkinson's disease? EMBO reports 96 15229644
2016 Parkin Regulates the Activity of Pyruvate Kinase M2. The Journal of biological chemistry 95 26975375
2004 Parkin attenuates manganese-induced dopaminergic cell death. Journal of neurochemistry 95 15189352
2018 PINK1-PARK2-mediated mitophagy in COPD and IPF pathogeneses. Inflammation and regeneration 93 30386443
2023 Unconventional initiation of PINK1/Parkin mitophagy by Optineurin. Molecular cell 90 37207627
2004 Ubiquitin, proteasome and parkin. Biochimica et biophysica acta 87 15571819
2016 A novel PINK1- and PARK2-dependent protective neuroimmune pathway in lethal sepsis. Autophagy 85 27754761
2015 Parkin Regulates Mitosis and Genomic Stability through Cdc20/Cdh1. Molecular cell 78 26387737
2004 Genetics of parkin-linked disease. Human genetics 70 14727181
2006 PARK2/PACRG polymorphisms and susceptibility to typhoid and paratyphoid fever. Clinical and experimental immunology 69 16734611
2012 Regulation of parkin and PINK1 by neddylation. Human molecular genetics 65 22388932
2015 A recurrent mutation in PARK2 is associated with familial lung cancer. American journal of human genetics 61 25640678
2021 Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson's Disease. Cells 60 33572534
2014 PINK1-mediated phosphorylation of Parkin boosts Parkin activity in Drosophila. PLoS genetics 59 24901221
2023 Hypoxia-induced GPCPD1 depalmitoylation triggers mitophagy via regulating PRKN-mediated ubiquitination of VDAC1. Autophagy 58 36803235
2001 Parkin is linked to the ubiquitin pathway. Journal of molecular medicine (Berlin, Germany) 58 11692161
2021 GAK and PRKCD are positive regulators of PRKN-independent mitophagy. Nature communications 57 34671015
2021 Mt-Keima detects PINK1-PRKN mitophagy in vivo with greater sensitivity than mito-QC. Autophagy 56 33685343
2018 Parkin mediates the ubiquitination of VPS35 and modulates retromer-dependent endosomal sorting. Human molecular genetics 55 29893854
2018 Loss of Microglial Parkin Inhibits Necroptosis and Contributes to Neuroinflammation. Molecular neurobiology 54 30074231
2022 Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation. Movement disorders : official journal of the Movement Disorder Society 53 35460111
2021 Assessing the relationship between monoallelic PRKN mutations and Parkinson's risk. Human molecular genetics 51 33448283
2019 PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons. Frontiers in cellular neuroscience 51 31333417
2015 Heterozygote carriers for CNVs in PARK2 are at increased risk of Parkinson's disease. Human molecular genetics 51 26188007
2015 Genomic and Functional Analysis of the E3 Ligase PARK2 in Glioma. Cancer research 50 25877876
2008 Combined kinase inhibition modulates parkin inactivation. Human molecular genetics 50 19050041
2004 N-myc regulates parkin expression. The Journal of biological chemistry 47 15078880
2018 Mitochondrial quality control mediated by PINK1 and PRKN: links to iron metabolism and tumor immunity. Autophagy 46 30252570
2017 Hexokinases link DJ-1 to the PINK1/parkin pathway. Molecular neurodegeneration 46 28962651
2015 Chemogenomic profiling of endogenous PARK2 expression using a genome-edited coincidence reporter. ACS chemical biology 44 25689131
2017 Post translational modification of Parkin. Biology direct 43 28222786
2004 How do Parkin mutations result in neurodegeneration? Current opinion in neurobiology 43 15194120
2024 Genotype-phenotype correlation in PRKN-associated Parkinson's disease. NPJ Parkinson's disease 42 38553467
2023 PA2G4/EBP1 ubiquitination by PRKN/PARKIN promotes mitophagy protecting neuron death in cerebral ischemia. Autophagy 42 37712850
2019 Metabolomics-based identification of metabolic alterations in PARK2. Annals of clinical and translational neurology 42 30911576
2018 PARK2 inhibits osteosarcoma cell growth through the JAK2/STAT3/VEGF signaling pathway. Cell death & disease 42 29515107
2020 PINK1 and Parkin: team players in stress-induced mitophagy. Biological chemistry 41 32297878
2015 USP8 and PARK2/parkin-mediated mitophagy. Autophagy 41 25700639
2015 Activation of the E3 ubiquitin ligase Parkin. Biochemical Society transactions 40 25849928
2020 Reduced astrocytic reactivity in human brains and midbrain organoids with PRKN mutations. NPJ Parkinson's disease 39 33298969
2020 Two different axes CALCOCO2-RB1CC1 and OPTN-ATG9A initiate PRKN-mediated mitophagy. Autophagy 38 32892694
2016 PINK1 and Parkin are genetic modifiers for FUS-induced neurodegeneration. Human molecular genetics 38 27794540
2015 Functions and characteristics of PINK1 and Parkin in cancer. Frontiers in bioscience (Landmark edition) 38 25553463
2017 Twenty years since the discovery of the parkin gene. Journal of neural transmission (Vienna, Austria : 1996) 37 28620835
2011 Restriction of trophic factors and nutrients induces PARKIN expression. Neurogenetics 37 22028146
2017 The synaptic function of parkin. Brain : a journal of neurology 36 28335015
2013 The reciprocal roles of PARK2 and mitofusins in mitophagy and mitochondrial spheroid formation. Autophagy 36 24162069
2011 Loss-of-function rodent models for parkin and PINK1. Journal of Parkinson's disease 35 23939304
2009 Regulation of DNA repair by parkin. Biochemical and biophysical research communications 35 19285961
2021 MITOL promotes cell survival by degrading Parkin during mitophagy. EMBO reports 34 33565245
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2023 Long-Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society 31 37926948
2019 PARK2 Suppresses Proliferation and Tumorigenicity in Non-small Cell Lung Cancer. Frontiers in oncology 31 31508359
2022 Genotype-phenotype correlation of Parkinson's disease with PRKN variants. Neurobiology of aging 29 35123805
2015 Expression pattern of parkin isoforms in lung adenocarcinomas. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 29 25656612
2010 Nonmotor symptoms in Parkin gene-related parkinsonism. Movement disorders : official journal of the Movement Disorder Society 29 20629119
2016 Pan-Cancer Analysis Links PARK2 to BCL-XL-Dependent Control of Apoptosis. Neoplasia (New York, N.Y.) 28 28038320
2025 Histone lactylation regulates PRKN-Mediated mitophagy to promote M2 Macrophage polarization in bladder cancer. International immunopharmacology 27 39854875
2019 The Transcription Factor Function of Parkin: Breaking the Dogma. Frontiers in neuroscience 27 30697141