ArticleThe EMBO journal2015
Disruption of the autoinhibited state primes the E3 ligase parkin for activation and catalysis.
Article in The EMBO journal, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 121 papers, 2 of them syntheses that pooled it.
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Who cites it
121 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- The molecular mechanisms of mitochondrial dynamics and mitophagy and their complex association with cancer drug resistance.Journal of translational medicine · 2025Pooled it
- Heterozygous PINK1 p.G411S increases risk of Parkinson's disease via a dominant-negative mechanism.Brain : a journal of neurology · 2017Pooled it
- Regulation and roles of mammalian mitophagy.Nature reviews. Molecular cell biology · 2026Review
- The role of phospho-ubiquitin in mitochondrial health and diseases.The Journal of biological chemistry · 2026Review
- Article
- Cis or trans: a puzzle of Parkin activation mechanism.Essays in biochemistry · 2026Review
- MCUB Inhibits PRKN-Dependent Mitophagic Degradation of PD-L1 to Promote Immune Evasion in Bladder Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Modulation of mitochondrial quality control in sepsis by traditional Chinese medicine: mechanistic insights and translational perspectives.Frontiers in pharmacology · 2026Review
- Activation of endogenous PRKN by structural derepression is linked to increased turnover of the E3 ubiquitin ligase.Autophagy · 2025Article
- Canonical and alternate mechanisms that regulate ubiquitylation by the E3 ligase parkin.Biochemical Society transactions · 2025Review
- A substrate-interacting region of Parkin directs ubiquitination of the mitochondrial GTPase Miro1.The Journal of cell biology · 2025Article
- Targeting mitophagy in neurodegenerative diseases.Nature reviews. Drug discovery · 2025Review
- Molecular Symphony of Mitophagy: Ubiquitin-Specific Protease-30 as a Maestro for Precision Management of Neurodegenerative Diseases.CNS neuroscience & therapeutics · 2025Review
- Exploring mitochondrial dynamics and localization under cellular stress: A comprehensive insight.Journal of biosciences · 2025Review
- Cooperative Substructure and Energetics of Allosteric Regulation of the Catalytic Core of the E3 Ubiquitin Ligase Parkin by Phosphorylated Ubiquitin.Biomolecules · 2024Article
- Activation of parkin by a molecular glue.Nature communications · 2024Article
- Cell-Based Covalent-Capture Deubiquitinase Assay for Inhibitor Discovery.ACS pharmacology & translational science · 2024Article
- Additional feedforward mechanism of Parkin activation via binding of phospho-UBL and RING0 ineLife · 2024Article
- Autoinhibited Protein Database: a curated database of autoinhibitory domains and their autoinhibition mechanisms.Database : the journal of biological databases and curation · 2024Article
- Naturally occurring hyperactive variants of human parkin.Communications biology · 2024Article
61 more citing papers are in PubMed but not listed here.
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13 authors.
Funding
Abstract
The PARK2 gene is mutated in 50% of autosomal recessive juvenile parkinsonism (ARJP) cases. It encodes parkin, an E3 ubiquitin ligase of the RBR family. Parkin exists in an autoinhibited state that is activated by phosphorylation of its N-terminal ubiquitin-like (Ubl) domain and binding of phosphoubiquitin. We describe the 1.8 Å crystal structure of human parkin in its fully inhibited state and identify the key interfaces to maintain parkin inhibition. We identify the phosphoubiquitin-binding interface, provide a model for the phosphoubiquitin-parkin complex and show how phosphorylation of the Ubl domain primes parkin for optimal phosphoubiquitin binding. Furthermore, we demonstrate that the addition of phosphoubiquitin leads to displacement of the Ubl domain through loss of structure, unveiling a ubiquitin-binding site used by the E2~Ub conjugate, thus leading to active parkin. We find the role of the Ubl domain is to prevent parkin activity in the absence of the phosphorylation signals, and propose a model for parkin inhibition, optimization for phosphoubiquitin recruitment, release of inhibition by the Ubl domain and engagement with an E2~Ub conjugate. Taken together, this model provides a mechanistic framework for activating parkin.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.