Affinage

PRKN

E3 ubiquitin-protein ligase parkin · UniProt O60260

Length
465 aa
Mass
51.6 kDa
Annotated
2026-06-10
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PRKN/Parkin is a RING-IBR-RING (RBR)-type E3 ubiquitin ligase that operates as the effector arm of a quality-control pathway clearing damaged mitochondria by selective autophagy (mitophagy), with loss-of-function mutations causing autosomal-recessive juvenile Parkinsonism (PMID:19029340, PMID:11692161). Parkin catalyzes ubiquitin transfer in collaboration with E2 conjugating enzymes (UbcH7/UbcH8), and AR-JP patient mutations abolish this activity (PMID:11692161). Mitochondrial depolarization causes PINK1 to accumulate on damaged organelles, where it is both necessary and sufficient to recruit cytosolic Parkin, placing PINK1 directly upstream in a linear pathway (PMID:20126261). Activation is conformational: PINK1 phosphorylates ubiquitin and the Parkin ubiquitin-like (Ubl) domain at Ser65; phospho-ubiquitin docks a RING1 pocket to release the autoinhibitory Ubl, and the phospho-Ubl then rebinds the unique parkin domain via a conserved activating element, liberating the catalytic RING2/Rcat domain for ubiquitin transfer (PMID:26161729, PMID:29995846, PMID:29967542). Once activated on the outer mitochondrial membrane, Parkin ubiquitinates a series of substrates including Miro1, VDAC1, and BNIP3L/Nix to mark mitochondria for clearance, arrest their axonal transport, and recruit autophagy receptors and the endosomal Rab cascade (RABGEF1–RAB5/RAB7A) that drives autophagic engulfment (PMID:25612572, PMID:27679849, PMID:30504269, PMID:32047033, PMID:29360040). This mitophagy program restrains STING-dependent type I interferon innate immunity, and its failure drives inflammation and dopaminergic neuron loss in vivo (PMID:30135585). Parkin activity is tuned by deubiquitinases that reverse its self-ubiquitination (USP8 removing K6-linked, USP33 removing multiple linkages to stabilize Parkin) (PMID:31432739, PMID:25700639), by activating neddylation (PMID:22388932), and by inactivating modifications including CKI/Cdk5 phosphorylation and S-nitrosylation (PMID:19050041, PMID:17017531); MITOL/MARCH5 ubiquitinates Parkin at K220 to control its abundance (PMID:33565245). Beyond mitophagy, Parkin ubiquitinates additional substrates affecting metabolism and survival, including PKM2, BCL-XL, the Pael receptor, synphilin-1, and intracellular Aβ1-42 (PMID:26975375, PMID:12846978, PMID:19483198, PMID:28038320, PMID:17017531). Small-molecule 'molecular glues' that enhance phospho-ubiquitin binding to RING0 can pharmacologically activate Parkin and partially rescue early-onset PD mutants (PMID:39300082).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2001 High

    Established Parkin's core biochemical identity as a RING-type E3 ubiquitin ligase whose activity is destroyed by disease mutations, defining the molecular lesion in AR-JP.

    Evidence In vitro ubiquitination reconstitution with purified components, E2 pairing, and patient mutation analysis

    PMID:11692161

    Open questions at the time
    • CDCrel-1 substrate relevance to neurodegeneration unresolved
    • did not define the physiological trigger for ligase activity
  2. 2008 High

    Revealed that Parkin's function is spatially gated — it is recruited from cytosol specifically to depolarized mitochondria and drives their autophagic elimination, linking the ligase to organelle quality control.

    Evidence Live-cell imaging and membrane-potential assays in mammalian cells

    PMID:19029340

    Open questions at the time
    • did not identify the upstream sensor of damage
    • OMM substrates ubiquitinated for mitophagy not yet mapped
  3. 2010 High

    Placed PINK1 upstream of Parkin by showing voltage-dependent PINK1 accumulation is necessary and sufficient for Parkin recruitment, defining a linear PINK1–Parkin mitophagy pathway.

    Evidence Genetic epistasis, microscopy, fractionation, Drosophila rescue

    PMID:20126261

    Open questions at the time
    • molecular signal transmitted from PINK1 to Parkin unknown at this stage
    • did not resolve the conformational activation mechanism
  4. 2015 High

    Solved how phospho-ubiquitin acts as the activating ligand, docking RING1 to release the autoinhibitory Ubl and exposing Ubl Ser65 for further phosphorylation — explaining the feed-forward activation switch.

    Evidence X-ray crystallography of Parkin–phosphoUb complex with mutagenesis and ubiquitination assays

    PMID:26161729

    Open questions at the time
    • did not show fate of released RING2 catalytic domain
    • ortholog structure required mammalian confirmation
  5. 2018 High

    Completed the activation model by showing the phospho-Ubl rebinds the UPD via a conserved activating element to release the catalytic RING2/Rcat domain, with full-length human and insect structures plus E2 capture.

    Evidence HDX-MS, 1.8 Å and complex crystallography, NMR, mutagenesis, in vitro ubiquitination

    PMID:29967542 PMID:29995846

    Open questions at the time
    • substrate engagement geometry on the mitochondrial surface not resolved
    • kinetics of activation in cellulo not quantified
  6. 2018 Medium

    Identified downstream effectors converting Parkin ubiquitination into autophagic engulfment, recruiting the RABGEF1–RAB5/RAB7A endosomal cascade and ATG9A vesicle assembly to damaged mitochondria.

    Evidence siRNA knockdown, Co-IP, microscopy, mitophagy assays in cultured cells

    PMID:29360040

    Open questions at the time
    • single lab; direct ubiquitin substrate recruiting RABGEF1 not defined
    • reciprocal validation absent
  7. 2018 Medium

    Resolved the upstream control of PINK1 stability, defining a PHB2–PARL–PGAM5 axis required to stabilize PINK1 and thereby permit Parkin and OPTN recruitment.

    Evidence Knockdown/overexpression epistasis, Co-IP, microscopy, mitophagy assays

    PMID:31177901

    Open questions at the time
    • single lab
    • direct biochemical interactions within the axis not fully reconstituted
  8. 2016 Medium

    Defined Miro as both a docking platform and a substrate, showing PINK1 phosphorylation of Miro promotes Parkin binding, Miro ubiquitination/degradation and arrest of mitochondrial axonal transport.

    Evidence Phosphomimetic mutagenesis, Co-IP, ubiquitination assays, axonal transport imaging; plus calcium-sensitive docking via Miro1 EF-hands

    PMID:27679849 PMID:30504269

    Open questions at the time
    • single lab per study
    • stoichiometry of the pre-damage Parkin–Miro pool unclear
  9. 2020 Medium

    Showed VDAC1 ubiquitination is dual-mode, with mono- versus poly-ubiquitination separating mitophagy from calcium/apoptosis control, validated by a PD mutation selectively losing monoubiquitination.

    Evidence Mutagenesis, calcium imaging, Drosophila models, patient mutation analysis

    PMID:32047033

    Open questions at the time
    • single lab
    • mechanism linking monoUb to MCU calcium flux not fully defined
  10. 2018 High

    Connected Parkin-driven mitophagy to suppression of innate immunity, showing STING deletion rescues inflammation and dopaminergic neuron loss in Prkn-deficient stressed mice.

    Evidence Multiple mouse knockout models, exercise/mtDNA-mutator stress, behavioral and histological readouts

    PMID:30135585

    Open questions at the time
    • molecular route from defective mitophagy to STING activation not fully detailed
    • human relevance of the inflammatory axis untested here
  11. 2021 Medium

    Identified regulators tuning Parkin levels and modification state — deubiquitinases (USP8, USP33), activating neddylation, inactivating CKI/Cdk5 phosphorylation and S-nitrosylation, and MITOL-mediated K220 ubiquitination controlling Parkin turnover.

    Evidence Deubiquitination/neddylation/kinase assays, mutagenesis, KO cell lines, mitophagy and cell-death readouts, PD tissue

    PMID:17017531 PMID:19050041 PMID:22388932 PMID:25700639 PMID:31432739 PMID:33565245

    Open questions at the time
    • each modification largely from a single lab
    • integrated hierarchy of these regulatory inputs unresolved
  12. 2023 Medium

    Expanded Parkin's substrate repertoire beyond canonical mitophagy to metabolic, apoptotic, ER-stress, and proteostatic targets (PKM2, BCL-XL, Pael receptor, synphilin-1, Aβ1-42, PA2G4, BNIP3L), broadening its role in neuronal and metabolic homeostasis.

    Evidence Co-IP, ubiquitination assays, in vivo KO/rescue models across multiple studies

    PMID:12846978 PMID:17017531 PMID:19483198 PMID:25612572 PMID:26975375 PMID:28038320 PMID:37712850

    Open questions at the time
    • substrate specificity determinants in vivo unclear
    • relative physiological weight of mitophagy versus non-mitochondrial substrates unresolved
  13. 2024 High

    Demonstrated Parkin is pharmacologically tractable, with small-molecule molecular glues enhancing phospho-ubiquitin binding at RING0 to activate the enzyme and partially rescue early-onset PD mutants.

    Evidence Crystallography, ITC, HDX-MS, ubiquitination and mitophagy assays with disease mutants

    PMID:39300082

    Open questions at the time
    • in vivo efficacy and selectivity not established
    • rescue of only a subset of disease mutants

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Parkin's diverse substrate selection and regulatory modifications are integrated in vivo to balance mitophagy, mitochondrial biogenesis, metabolism, and neuronal survival remains unresolved.
  • no unified model ranking the physiological importance of competing substrates
  • tissue-specific regulatory hierarchy of activating/inactivating modifications undefined
  • structural basis of substrate engagement on the mitochondrial surface unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016874 ligase activity 3 GO:0031386 protein tag activity 3 GO:0098772 molecular function regulator activity 1
Localization
GO:0005739 mitochondrion 4 GO:0005829 cytosol 3
Pathway
R-HSA-9612973 Autophagy 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-168256 Immune System 1
Partners
BCL-XLBNIP3LMIRO1PINK1PKM2USP33USP8VDAC1

Evidence

Reading pass · 30 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, after which it mediates engulfment of mitochondria by autophagosomes and their selective elimination (mitophagy). Live-cell imaging and mitochondrial membrane potential assays in mammalian cells with Parkin overexpression/loss-of-function The Journal of cell biology High 19029340
2010 PINK1 accumulates selectively on damaged (depolarized) mitochondria via voltage-dependent proteolysis; PINK1 accumulation is both necessary and sufficient for Parkin recruitment to mitochondria, placing PINK1 upstream of Parkin in a linear epistatic pathway controlling mitophagy. Disease-causing mutations in PINK1 and Parkin disrupt Parkin recruitment at distinct steps. Genetic epistasis (PINK1/Parkin mutant cell lines), fluorescence microscopy, biochemical fractionation, Drosophila genetic rescue PLoS biology High 20126261
2015 Crystal structure of Parkin (Pediculus humanus ortholog) in complex with Ser65-phosphorylated ubiquitin (phosphoUb) reveals: (1) a conserved phosphate-binding pocket on RING1 that docks phosphoUb; (2) phosphoUb binding straightens a RING1 helix causing conformational changes that release the Ubl domain from the Parkin core; (3) Ubl release exposes Ubl Ser65 to PINK1 phosphorylation; (4) Ubl phosphorylation further stabilizes an open, active Parkin conformation. The Ubl domain acts as both an inhibitory and activating element. X-ray crystallography, mutagenesis, biochemical ubiquitination assays Nature High 26161729
2018 Full activation mechanism of Parkin: hydrogen-deuterium exchange MS reveals large-scale domain rearrangement upon PINK1-mediated phosphorylation; the phospho-Ubl rebinds to the Parkin core at the unique parkin domain (UPD) using a phosphate-binding pocket (lined by AR-JP mutations), releasing the catalytic RING2 domain. A conserved linker 'activating element' (ACT) between Ubl and UPD mimics RING2 interactions to aid RING2 release. 1.8 Å crystal structure of phosphorylated human Parkin confirms this binding site. Hydrogen-deuterium exchange mass spectrometry, X-ray crystallography (1.8 Å), mutagenesis Nature High 29995846
2018 Crystal structure of phosphorylated Bactrocera dorsalis Parkin in complex with phospho-ubiquitin and an E2 ubiquitin-conjugating enzyme reveals the key activating step: movement of the phospho-Ubl domain and release of the catalytic RING2 domain. HDX and NMR experiments confirm this mechanism extends to mammalian Parkin. X-ray crystallography, hydrogen/deuterium exchange, NMR, in vitro ubiquitination assays Nature structural & molecular biology High 29967542
2018 Parkin and PINK1-mediated mitophagy restrains innate immunity (STING-dependent type I interferon response). In Prkn−/− mice, exhaustive exercise or mtDNA mutation triggers inflammation that is completely rescued by concurrent STING loss. Loss of dopaminergic neurons and motor defects in aged Prkn−/−;mutator mice are also rescued by STING deletion. Mouse knockout models (Prkn−/−, Pink1−/−, STING−/−), exhaustive exercise stress, mtDNA mutator mouse, behavioral and histological analyses, cytokine measurements Nature High 30135585
2015 BNIP3L/Nix is a substrate of PARK2/Parkin; Parkin ubiquitinates BNIP3L, which recruits NBR1 to mitochondria to target them for degradation. BNIP3L rescues mitochondrial defects in pink1 mutant Drosophila but not in park mutant Drosophila, placing BNIP3L downstream of Parkin. Co-immunoprecipitation, ubiquitination assays, Drosophila genetic rescue, knockdown/overexpression in mammalian cells Human molecular genetics Medium 25612572
2016 Parkin interacts with and ubiquitinates pyruvate kinase M2 (PKM2) both in vitro and in vivo; ubiquitination does not affect PKM2 stability but decreases its enzymatic activity, thereby regulating glycolysis. The interaction is enhanced during glucose starvation. Biochemical purification, Co-IP (in vitro and in vivo), ubiquitination assay, enzymatic activity assay The Journal of biological chemistry Medium 26975375
2016 PINK1 phosphorylation of Miro on S156 promotes Parkin interaction with Miro, stimulates Miro ubiquitination and degradation, recruits Parkin to mitochondria, and via Parkin arrests axonal transport of mitochondria. Phosphomimetic T298E/T299E on Miro inhibits PINK1-induced Miro ubiquitination and Parkin recruitment, acting dominantly over S156E. Phosphomimetic mutations, Co-IP, ubiquitination assays, axonal transport imaging in neurons Proceedings of the National Academy of Sciences of the United States of America Medium 27679849
2018 Miro1 serves as a calcium-sensitive docking site for Parkin on mitochondria: a small pool of Parkin interacts with Miro1 before mitochondrial damage occurs, independently of PINK1 and without ubiquitination. After damage and PINK1 accumulation, this Parkin pool is activated, leading to Miro1 ubiquitination and degradation. Knockdown of Miro proteins reduces Parkin translocation and mitophagy. Miro1 EF-hand (calcium-sensing) domains control Miro1 ubiquitination and Parkin recruitment. Co-immunoprecipitation, fluorescence imaging, siRNA knockdown, EF-hand domain mutagenesis, mitophagy assays The EMBO journal Medium 30504269
2019 USP33/VDU1 is a deubiquitinase for Parkin, localizes to the outer mitochondrial membrane, and removes K6-, K11-, K48-, and K63-linked ubiquitin conjugates from Parkin, predominantly at Lys435. USP33 knockdown increases both K48- and K63-linked Parkin ubiquitination, stabilizes Parkin, and enhances its translocation to depolarized mitochondria, increasing mitophagy. Co-IP, in vitro deubiquitination assays, site-directed mutagenesis (K435R), siRNA knockdown, mitophagy assays Autophagy Medium 31432739
2015 USP8 deubiquitinase interacts with Parkin and preferentially removes K6-linked ubiquitin conjugates from Parkin. USP8 silencing leads to persistence of K6-linked Parkin ubiquitin conjugates, delaying Parkin translocation to damaged mitochondria and completion of mitophagy. Co-IP, ubiquitin linkage analysis, USP8 siRNA knockdown, mitophagy assays Autophagy Medium 25700639
2020 VDAC1 is ubiquitinated by Parkin in a PINK1-dependent manner in two modes: monoubiquitination (at K274) and polyubiquitination. Polyubiquitination deficiency impairs mitophagy. Monoubiquitination deficiency (K274R) promotes apoptosis by augmenting mitochondrial calcium uptake through the MCU channel. A PD patient mutation T415N in Parkin lacks VDAC1 monoubiquitination activity while retaining polyubiquitination, and fails to rescue PD phenotypes in Drosophila. Ubiquitination assays, site-directed mutagenesis, calcium imaging, Drosophila transgenic models, patient mutation analysis Proceedings of the National Academy of Sciences of the United States of America Medium 32047033
2018 RABGEF1, an upstream regulator 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 encapsulation of mitochondria by autophagic membranes. siRNA knockdown, Co-IP, fluorescence microscopy in mammalian cultured cells, mitophagy assays eLife Medium 29360040
2019 PHB2 (prohibitin 2, inner mitochondrial membrane protein) is required for PINK1 stabilization on mitochondria and subsequent Parkin recruitment. PHB2 depletion destabilizes PINK1 and blocks Parkin, ubiquitin, and OPTN recruitment. The mechanism involves the PARL protease (activated upon PHB2 depletion) and PGAM5 (processed by PARL), defining a PHB2-PARL-PGAM5-PINK1 axis upstream of Parkin. siRNA knockdown, overexpression, Co-IP, fluorescence microscopy, mitophagy assays in MEFs and cancer cells Autophagy Medium 31177901
2012 Parkin is neddylated (conjugated with NEDD8), and neddylation increases Parkin's E3 ligase activity. The PD neurotoxin MPP+ inhibits neddylation of Parkin. Expression of dAPP-BP1 (NEDD8 activation enzyme subunit) in Drosophila suppresses abnormalities induced by dPINK1 RNAi. Neddylation assays, E3 ligase activity assay, MPP+ treatment, Drosophila genetics Human molecular genetics Medium 22388932
2008 Combined phosphorylation of Parkin by both casein kinase I and cyclin-dependent kinase 5 (Cdk5) decreases Parkin solubility, causing its aggregation and inactivation. Combined kinase inhibition partially reverses aggregation of pathogenic Parkin point mutants in cultured cells. Enhanced Parkin phosphorylation is detected in brain areas of sporadic PD patients, correlating with elevated p25 (Cdk5 activator) levels. Kinase activity assays, solubility fractionation, cell-based aggregation assays, immunohistochemistry of PD brain tissue Human molecular genetics Medium 19050041
2003 Parkin ubiquitinates the Pael (parkin-associated endothelin receptor-like) receptor, an ER-resident protein prone to unfolding, using ER-resident E2s, and promotes its degradation, thereby suppressing ER stress-induced cell death. Insoluble Pael receptor accumulates in AR-JP patient brains. Yeast two-hybrid, in vitro ubiquitination assay with ER-resident E2s, cell death assays, post-mortem patient brain analysis Annals of the New York Academy of Sciences Medium 12846978
2009 Parkin promotes ubiquitination and proteasomal degradation of intracellular Aβ1-42. Parkin expression reduces intracellular Aβ1-42 levels and protects against its toxicity; incubation of Aβ1-42 cell lysates with ubiquitin in the presence of Parkin generates Aβ-ubiquitin complexes. Proteasomal inhibition blocks Parkin's effect on Aβ levels. Lentiviral overexpression, ubiquitination assay, proteasome inhibition, in vivo co-injection in rat motor cortex Human molecular genetics Medium 19483198
2009 Parkin is essential for optimal DNA excision 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. DNA repair assays, Co-IP with PCNA, transfection of wild-type vs. mutant Parkin, cell viability assays Biochemical and biophysical research communications Low 19285961
2016 PARK2/Parkin directly binds to and ubiquitinates BCL-XL, leading to its degradation. Inactivation of PARK2 leads to aberrant accumulation of BCL-XL in vitro and in vivo; cancer-specific PARK2 mutations abrogate BCL-XL ubiquitination. PARK2 modulates mitochondrial depolarization and apoptosis in a BCL-XL-dependent manner. Co-IP, ubiquitination assays, in vivo mouse models, cancer mutant analysis Neoplasia Medium 28038320
2021 MITOL/MARCH5 (mitochondrial ubiquitin ligase) ubiquitinates Parkin at lysine 220, promoting its proteasomal degradation. MITOL deletion leads to accumulation of phosphorylated active Parkin in the ER, resulting in FKBP38 degradation and enhanced cell death. MITOL thereby fine-tunes mitophagy by controlling Parkin quantity and blocks Parkin-induced cell death by protecting FKBP38. Ubiquitination assays, site-directed mutagenesis (K220), MITOL deletion cell lines, immunofluorescence, cell death assays EMBO reports Medium 33565245
2023 PA2G4/EBP1 is ubiquitinated on lysine 376 by PRKN/Parkin on damaged mitochondria; ubiquitinated PA2G4 then interacts with SQSTM1/p62 to induce mitophagy, protecting neurons from cerebral ischemia-reperfusion injury. Co-IP, ubiquitination assay with site-directed mutagenesis (K376), neuron-specific knockout mice (MCAO model), AAV rescue Autophagy Medium 37712850
2014 Parkin promotes Drp1-dependent mitochondrial fission by a mechanism requiring dephosphorylation of Drp1 serine 637 via the calcium/calmodulin/calcineurin pathway. Drp1 and Parkin are co-recruited to mitochondria in proximity of PINK1 following depolarization (FRET imaging). The outer mitochondrial adaptor MiD51 plays a major role in Drp1 recruitment and Parkin-dependent mitophagy. FRET imaging, calcineurin pathway inhibitors, Parkin/PINK1 mutant cell lines, mitochondrial morphology analysis Biochimica et biophysica acta Medium 24878071
2022 Park2-deficient white adipocytes show reduced mitophagy but increased mitochondrial DNA content and mitochondrial function due to elevated mitochondrial biogenesis via Pgc1α stabilization through mitochondrial superoxide-activated Nqo1. Parkin therefore balances mitophagy and Pgc1α-mediated mitochondrial biogenesis in white adipocytes. Adipose tissue-specific Park2 knockout mice, mitophagy assays, Nqo1 overexpression, in vitro and in vivo metabolic assays Nature communications Medium 36333379
2024 Small molecule allosteric modulators act as 'molecular glues' enhancing phospho-ubiquitin (pUb) binding to and activation of Parkin. Crystal structure of Parkin–pUb complex with compound BIO-1975900 shows it binds next to pUb on RING0, contacting both proteins. HDX-MS confirms activation occurs via release of the catalytic Rcat domain. The compounds partially rescue activity of EOPD Parkin mutants R42P and V56E in organello and mitophagy assays. X-ray crystallography, isothermal titration calorimetry, ubiquitination assays, HDX-MS, organello and cell-based mitophagy assays Nature communications High 39300082
2006 Parkin ubiquitinates synphilin-1 (the α-synuclein interacting protein); co-expression of α-synuclein, synphilin-1, and Parkin forms Lewy-body-like ubiquitin-positive cytosolic inclusions. Nitric oxide inhibits Parkin's E3 ligase activity and its neuroprotective function via S-nitrosylation both in vitro and in vivo. Ubiquitination assays, co-transfection/inclusion body formation assay, S-nitrosylation assay in vitro and in vivo Journal of neural transmission. Supplementum Medium 17017531
2020 Bcl-xL physically binds Parkin in the cytoplasm (FRET imaging) and also directly interacts with PINK1 on mitochondria (Co-IP), thereby inhibiting PINK1/Parkin-dependent mitophagy by preventing Parkin accumulation on mitochondria via two mechanisms: (1) cytoplasmic sequestration of Parkin, and (2) interference with PINK1 on the outer mitochondrial membrane. Co-IP, FRET imaging, FLIP analysis, Western blot, fluorescence microscopy in HeLa and HEK293T cells The international journal of biochemistry & cell biology Low 32088314
2017 Parkin accelerates microtubule aging in its absence: PARK2 knockout mice show accelerated over-acetylation of the microtubule system in dopaminergic neurons and fibers, preceding mitochondrial transport defects. Parkin deficiency causes fragmentation of stable microtubules in PC12 cells and iPSC-derived midbrain neurons. Paclitaxel (microtubule-stabilizing agent) rescues mitochondrial mobility defects caused by Parkin loss. PARK2 KO mouse histology, immunofluorescence of acetylated tubulin, mitochondrial transport assays, paclitaxel rescue, iPSC-derived neurons Neurobiology of aging Medium 29040870
2001 Parkin functions as a RING-type E3 ubiquitin ligase (via its RING-IBR-RING motif), collaborating with E2 ubiquitin-conjugating enzymes UbcH7 or UbcH8. AR-JP patient mutations abolish parkin's E3 ligase activity. CDCrel-1, a synaptic vesicle-associated protein, was identified as a substrate for Parkin. In vitro ubiquitination assays with purified components, patient mutation analysis, substrate identification by biochemical pulldown Journal of molecular medicine (Berlin, Germany) High 11692161

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 3329 19029340
2010 PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS biology 2405 20126261
2018 Parkin and PINK1 mitigate STING-induced inflammation. Nature 1074 30135585
2015 Mechanism of phospho-ubiquitin-induced PARKIN activation. Nature 394 26161729
2020 PINK1/PARKIN signalling in neurodegeneration and neuroinflammation. Acta neuropathologica communications 387 33168089
2019 PHB2 (prohibitin 2) promotes PINK1-PRKN/Parkin-dependent mitophagy by the PARL-PGAM5-PINK1 axis. Autophagy 342 31177901
2018 Mechanism of parkin activation by PINK1. Nature 318 29995846
2014 Parkin and PINK1: much more than mitophagy. Trends in neurosciences 316 24735649
2011 Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxidants & redox signaling 298 21194381
2017 PINK1 and Parkin: emerging themes in mitochondrial homeostasis. Current opinion in cell biology 275 28437683
2016 Mechanisms of mitophagy: PINK1, Parkin, USP30 and beyond. Free radical biology & medicine 265 27094585
2018 PINK1-PRKN/PARK2 pathway of mitophagy is activated to protect against renal ischemia-reperfusion injury. Autophagy 260 29172924
2016 Parkin and mitophagy in cancer. Oncogene 233 27593930
2018 PINK1 and PARK2 Suppress Pancreatic Tumorigenesis through Control of Mitochondrial Iron-Mediated Immunometabolism. Developmental cell 224 30100261
2021 Regulation of PRKN-independent mitophagy. Autophagy 203 33570005
2015 The mitochondrial protein BNIP3L is the substrate of PARK2 and mediates mitophagy in PINK1/PARK2 pathway. Human molecular genetics 194 25612572
2018 PRKN-regulated mitophagy and cellular senescence during COPD pathogenesis. Autophagy 192 30290714
2015 Parkin structure and function. The FEBS journal 192 25712550
2018 No Parkin Zone: Mitophagy without Parkin. Trends in cell biology 190 30115557
2020 Decision between mitophagy and apoptosis by Parkin via VDAC1 ubiquitination. Proceedings of the National Academy of Sciences of the United States of America 187 32047033
2011 Regulation of PINK1-Parkin-mediated mitophagy. Autophagy 154 21187721
2018 Mechanism of parkin activation by phosphorylation. Nature structural & molecular biology 152 29967542
2019 SQSTM1/p62 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin in mitophagy. Autophagy 145 31339428
2018 Endosomal Rab cycles regulate Parkin-mediated mitophagy. eLife 141 29360040
2020 Mitochondrial damage-associated inflammation highlights biomarkers in PRKN/PINK1 parkinsonism. Brain : a journal of neurology 140 33029617
2012 Systematic review and UK-based study of PARK2 (parkin), PINK1, PARK7 (DJ-1) and LRRK2 in early-onset Parkinson's disease. Movement disorders : official journal of the Movement Disorder Society 135 22956510
2004 Parkin genetics: one model for Parkinson's disease. Human molecular genetics 135 14976155
2016 Miro phosphorylation sites regulate Parkin recruitment and mitochondrial motility. Proceedings of the National Academy of Sciences of the United States of America 133 27679849
2014 Functional interplay between Parkin and Drp1 in mitochondrial fission and clearance. Biochimica et biophysica acta 131 24878071
2016 Parkin and PINK1 functions in oxidative stress and neurodegeneration. Brain research bulletin 125 28017782
2020 The PINK1-Parkin axis: An Overview. Neuroscience research 115 31982458
2018 Miro proteins prime mitochondria for Parkin translocation and mitophagy. The EMBO journal 114 30504269
2019 USP33 deubiquitinates PRKN/parkin and antagonizes its role in mitophagy. Autophagy 112 31432739
2004 Parkin gene alterations in hepatocellular carcinoma. Genes, chromosomes & cancer 105 15101042
2016 Parkin Regulates the Activity of Pyruvate Kinase M2. The Journal of biological chemistry 97 26975375
2006 Parkin: a multifaceted ubiquitin ligase. Biochemical Society transactions 97 17052189
2023 Unconventional initiation of PINK1/Parkin mitophagy by Optineurin. Molecular cell 96 37207627
2004 How does parkin ligate ubiquitin to Parkinson's disease? EMBO reports 96 15229644
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 94 30386443
2004 Parkin and relatives: the RBR family of ubiquitin ligases. Physiological genomics 94 15152079
2009 Parkin promotes intracellular Abeta1-42 clearance. Human molecular genetics 88 19483198
2016 A novel PINK1- and PARK2-dependent protective neuroimmune pathway in lethal sepsis. Autophagy 87 27754761
2004 Ubiquitin, proteasome and parkin. Biochimica et biophysica acta 87 15571819
2001 Parkin and Parkinson's disease. Current opinion in neurology 85 11470964
2015 Parkin-dependent mitophagy in the heart. Journal of molecular and cellular cardiology 78 26611886
2016 Parkin Regulation and Neurodegenerative Disorders. Frontiers in aging neuroscience 71 26793099
2004 Genetics of parkin-linked disease. Human genetics 70 14727181
2012 Regulation of parkin and PINK1 by neddylation. Human molecular genetics 66 22388932
2023 Hypoxia-induced GPCPD1 depalmitoylation triggers mitophagy via regulating PRKN-mediated ubiquitination of VDAC1. Autophagy 63 36803235
2021 Mt-Keima detects PINK1-PRKN mitophagy in vivo with greater sensitivity than mito-QC. Autophagy 62 33685343
2021 Interaction between Parkin and α-Synuclein in PARK2-Mediated Parkinson's Disease. Cells 61 33572534
2006 Parkin and defective ubiquitination in Parkinson's disease. Journal of neural transmission. Supplementum 61 17017531
2021 GAK and PRKCD are positive regulators of PRKN-independent mitophagy. Nature communications 60 34671015
2022 Heterozygous PRKN mutations are common but do not increase the risk of Parkinson's disease. Brain : a journal of neurology 59 35640906
2001 Parkin is linked to the ubiquitin pathway. Journal of molecular medicine (Berlin, Germany) 58 11692161
2022 Parkin Deficiency Impairs Mitochondrial DNA Dynamics and Propagates Inflammation. Movement disorders : official journal of the Movement Disorder Society 56 35460111
2018 Loss of Microglial Parkin Inhibits Necroptosis and Contributes to Neuroinflammation. Molecular neurobiology 54 30074231
2021 Assessing the relationship between monoallelic PRKN mutations and Parkinson's risk. Human molecular genetics 52 33448283
2019 PARK2 Mutation Causes Metabolic Disturbances and Impaired Survival of Human iPSC-Derived Neurons. Frontiers in cellular neuroscience 51 31333417
2008 Combined kinase inhibition modulates parkin inactivation. Human molecular genetics 51 19050041
2012 Involvement and interplay of Parkin, PINK1, and DJ1 in neurodegenerative and neuroinflammatory disorders. Free radical biology & medicine 49 22687462
2024 Genotype-phenotype correlation in PRKN-associated Parkinson's disease. NPJ Parkinson's disease 47 38553467
2023 PA2G4/EBP1 ubiquitination by PRKN/PARKIN promotes mitophagy protecting neuron death in cerebral ischemia. Autophagy 47 37712850
2017 Hexokinases link DJ-1 to the PINK1/parkin pathway. Molecular neurodegeneration 47 28962651
2004 N-myc regulates parkin expression. The Journal of biological chemistry 47 15078880
2003 Parkin and endoplasmic reticulum stress. Annals of the New York Academy of Sciences 47 12846978
2017 Post translational modification of Parkin. Biology direct 44 28222786
2020 PINK1 and Parkin: team players in stress-induced mitophagy. Biological chemistry 43 32297878
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
2015 USP8 and PARK2/parkin-mediated mitophagy. Autophagy 42 25700639
2017 Parkin absence accelerates microtubule aging in dopaminergic neurons. Neurobiology of aging 41 29040870
2015 Activation of the E3 ubiquitin ligase Parkin. Biochemical Society transactions 40 25849928
2022 Parkin regulates adiposity by coordinating mitophagy with mitochondrial biogenesis in white adipocytes. Nature communications 39 36333379
2020 Two different axes CALCOCO2-RB1CC1 and OPTN-ATG9A initiate PRKN-mediated mitophagy. Autophagy 38 32892694
2015 Functions and characteristics of PINK1 and Parkin in cancer. Frontiers in bioscience (Landmark edition) 38 25553463
2017 The synaptic function of parkin. Brain : a journal of neurology 37 28335015
2017 Twenty years since the discovery of the parkin gene. Journal of neural transmission (Vienna, Austria : 1996) 37 28620835
2013 The reciprocal roles of PARK2 and mitofusins in mitophagy and mitochondrial spheroid formation. Autophagy 36 24162069
2024 Activation of parkin by a molecular glue. Nature communications 35 39300082
2022 RNA-binding protein YBX1 promotes brown adipogenesis and thermogenesis via PINK1/PRKN-mediated mitophagy. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 35 35195911
2021 MITOL promotes cell survival by degrading Parkin during mitophagy. EMBO reports 35 33565245
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
2024 A mutational atlas for Parkin proteostasis. Nature communications 34 38378758
2020 PRCC-TFE3 fusion-mediated PRKN/parkin-dependent mitophagy promotes cell survival and proliferation in PRCC-TFE3 translocation renal cell carcinoma. Autophagy 34 33019842
2025 Histone lactylation regulates PRKN-Mediated mitophagy to promote M2 Macrophage polarization in bladder cancer. International immunopharmacology 33 39854875
2023 Long-Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease. Movement disorders : official journal of the Movement Disorder Society 32 37926948
2019 PARK2 Suppresses Proliferation and Tumorigenicity in Non-small Cell Lung Cancer. Frontiers in oncology 31 31508359
2006 Parkin blushed by PINK1. Neuron 31 16701203
2016 Pan-Cancer Analysis Links PARK2 to BCL-XL-Dependent Control of Apoptosis. Neoplasia (New York, N.Y.) 29 28038320
2015 Expression pattern of parkin isoforms in lung adenocarcinomas. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 29 25656612
2024 Canagliflozin Mitigates Diabetic Cardiomyopathy through Enhanced PINK1-Parkin Mitophagy. International journal of molecular sciences 28 39000117
2020 Bcl-xL inhibits PINK1/Parkin-dependent mitophagy by preventing mitochondrial Parkin accumulation. The international journal of biochemistry & cell biology 27 32088314
2019 The Transcription Factor Function of Parkin: Breaking the Dogma. Frontiers in neuroscience 27 30697141
2017 Parkin-independent mitophagy-FKBP8 takes the stage. EMBO reports 27 28515082
2016 Central Parkin: The evolving role of Parkin in the heart. Biochimica et biophysica acta 26 26992930
2023 Parkin and mitochondrial signalling. Cellular signalling 25 36803775
2021 A mechanistic review of Parkin activation. Biochimica et biophysica acta. General subjects 24 33753174

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