ArticleLife science alliance2023
Structure-based design and characterization of Parkin-activating mutations.
Article in Life science alliance, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 29 citations in OpenAlex.
- DYRK1A and Parkinson's disease, facts and hypotheses.Neurobiology of disease · 2026Review
- Targeting of kinases to treat neurodegenerative diseases.Pharmacological reviews · 2026Review
- Autophagy and mitophagy at the synapse and beyond: implications for learning, memory and neurological disorders.Autophagy · 2026Review
- Activation of endogenous PRKN by structural derepression is linked to increased turnover of the E3 ubiquitin ligase.Autophagy · 2025Article
- The absence of Parkin in hTau mice leads to synaptic mitochondrial dysfunction, alterations to the synaptic proteome, and increased phosphorylated tau in the Hippocampus.Neurobiology of disease · 2025Article
- Targeting mitophagy in neurodegenerative diseases.Nature reviews. Drug discovery · 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
- Naturally occurring hyperactive variants of human parkin.Communications biology · 2024Article
- Capturing the catalytic intermediates of parkin ubiquitination.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Unveiling the molecular mechanisms of the type IX secretion system's response regulator: Structural and functional insights.PNAS nexus · 2024Article
- Exploring the Role of Ubiquitin-Proteasome System in the Pathogenesis of Parkinson's Disease.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Genetic Encoding of Phosphorylated Amino Acids into Proteins.Chemical reviews · 2024Review
- PRKN-linked familial Parkinson's disease: cellular and molecular mechanisms of disease-linked variants.Cellular and molecular life sciences : CMLS · 2024Review
- Discovery and characterization of noncanonical E2-conjugating enzymes.Science advances · 2024Article
- In Silico Investigation of Parkin-Activating Mutations Using Simulations and Network Modeling.Biomolecules · 2024Article
- Tom20 gates PINK1 activity and mediates its tethering of the TOM and TIM23 translocases upon mitochondrial stress.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Design and high-throughput implementation of MALDI-TOF/MS-based assays for Parkin E3 ligase activity.Cell reports methods · 2024Article
- A mutational atlas for Parkin proteostasis.Nature communications · 2024Article
- A PINK1 input threshold arises from positive feedback in the PINK1/Parkin mitophagy decision circuit.Cell reports · 2023Article
Corrections and comments
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Authors and funding
11 authors at 5 institutions in 4 countries.
Funding
Abstract
Autosomal recessive mutations in the Parkin gene cause Parkinson's disease. Parkin encodes an ubiquitin E3 ligase that functions together with the kinase PINK1 in a mitochondrial quality control pathway. Parkin exists in an inactive conformation mediated by autoinhibitory domain interfaces. Thus, Parkin has become a target for the development of therapeutics that activate its ligase activity. Yet, the extent to which different regions of Parkin can be targeted for activation remained unknown. Here, we have used a rational structure-based approach to design new activating mutations in both human and rat Parkin across interdomain interfaces. Out of 31 mutations tested, we identified 11 activating mutations that all cluster near the RING0:RING2 or REP:RING1 interfaces. The activity of these mutants correlates with reduced thermal stability. Furthermore, three mutations V393D, A401D, and W403A rescue a Parkin S65A mutant, defective in mitophagy, in cell-based studies. Overall our data extend previous analysis of Parkin activation mutants and suggests that small molecules that would mimic RING0:RING2 or REP:RING1 destabilisation offer therapeutic potential for Parkinson's disease patients harbouring select Parkin mutations.
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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.