ArticleCommunications biology2023
Minimal mechanistic component of HbYX-dependent proteasome activation that reverses impairment by neurodegenerative-associated oligomers.
Article in Communications biology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 26 citations in OpenAlex.
- Stimulating proteasomal degradation in human proteinopathies.The FEBS journal · 2026Review
- Blm10/PA200-Activated 20S Proteasomes Promote α-Synuclein Degradation and Bypass Proteasome Inhibition in Parkinson's Disease Models.Aging cell · 2026Article
- Breaking the proteasome balance: α-synuclein and the ubiquitin-proteasome system.Frontiers in cell and developmental biology · 2026Review
- Multilayer modulation of the proteasome: new strategies for neuroprotection.Frontiers in molecular neuroscience · 2026Article
- Tetra-anionic porphyrin mimics protein-protein interactions between regulatory particles and the catalytic core, allosterically activating human 20S proteasome.Journal of enzyme inhibition and medicinal chemistry · 2025Article
- Hyperactive 20Science advances · 2025Article
- Recent Advancements in 20S Proteasome Enhancement: Degradation of Undruggable Targets.ACS medicinal chemistry letters · 2025Review
- Article
- Novel strategies for targeting tau oligomers in neurodegenerative diseases.Journal of neurology · 2025Review
- ProEnd: a comprehensive database for identifying HbYX motif-containing proteins across the tree of life.BMC genomics · 2024Article
- ProEnd: A Comprehensive Database for Identifying HbYX Motif-Containing Proteins Across the Tree of Life.bioRxiv : the preprint server for biology · 2024Article
- Rpt5-Derived Analogs Stimulate Human Proteasome Activity in Cells and Degrade Proteins Forming Toxic Aggregates in Age-Related Diseases.International journal of molecular sciences · 2024Article
- Differential Interactions of the Proteasome Inhibitor PI31 with Constitutive and Immuno-20S Proteasomes.Biochemistry · 2024Article
- Therapeutic potential of archaeal unfoldase PANet and the gateless T20S proteasome in P23H rhodopsin retinitis pigmentosa mice.PloS one · 2024Article
- Mechanisms of ubiquitin-independent proteasomal degradation and their roles in age-related neurodegenerative disease.Frontiers in cell and developmental biology · 2024Review
- High resolution structures define divergent and convergent mechanisms of archaeal proteasome activation.Communications biology · 2023Article
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3 authors at 1 institution in 1 country.
Funding
Abstract
The implication of reduced proteasomal function in neurodegenerative diseases combined with studies showing the protective effects of increasing proteasome activity in animal models highlight the need to understand the capacity for proteasome activation by small molecules. The C-terminal HbYX motif is present on many proteasome binding proteins and functions to tether activators to the 20S core particle. Previous studies have shown that peptides with a HbYX motif can autonomously activate 20S gate-opening to allow protein degradation. In this study, through an iterative process of peptide synthesis, we design a HbYX-like dipeptide mimetic that represents only the fundamental components of the HbYX motif. The mimetic robustly induces gate-opening in archaeal, yeast, and mammalian proteasomes. We identify multiple proteasome α subunit residues in the archaeal proteasome involved in HbYX-dependent activation. When stimulated by the mimetic, the mammalian 20S can degrade unfolded proteins such as tau. Findings using our peptide mimetic suggest the HbYX-dependent mechanism requires cooperative binding in at least two intersubunit pockets of the α ring. Most significantly, our peptide mimetic reverses proteasome impairment by neurodegenerative disease-associated oligomers. Collectively, these results validate HbYX-like molecules as having robust potential to stimulate proteasome function, which are potentially useful for treating neurodegenerative diseases.
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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.