ArticleThe Journal of biological chemistry2018
Profilin reduces aggregation and phase separation of huntingtin N-terminal fragments by preferentially binding to soluble monomers and oligomers.
Article in The Journal of biological chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 135 citations in OpenAlex.
- Review
- Article
- Surface-modified protein crowders influence mutant huntingtin exon 1 aggregation via crowding effects, crowder association, and crowder solution stability.Protein science : a publication of the Protein Society · 2025Article
- A Coarse-Grained MD Model for Disorder-To-Order Transitions in PolyQ Aggregation.Journal of chemical theory and computation · 2025Article
- Structure of the Huntingtin F-actin complex reveals its role in cytoskeleton organization.Science advances · 2025Article
- Profilin and Non-Canonical Wnt Signaling: Coordinating Cytoskeletal Dynamics from Development to Disease.Journal of developmental biology · 2025Review
- Tunable metastability of condensates reconciles their dual roles in amyloid fibril formation.Molecular cell · 2025Article
- Inhibitor-based modulation of huntingtin aggregation mechanisms mitigates fibril-induced cellular stress.Nature communications · 2025Article
- Site-Specific Incorporation of Fluorinated Prolines into Proteins and Their Impact on Neighbouring Residues.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Pathological Involvement of Protein Phase Separation and Aggregation in Neurodegenerative Diseases.International journal of molecular sciences · 2024Review
- Oncogenic p53 triggers amyloid aggregation of p63 and p73 liquid droplets.Communications chemistry · 2024Article
- Two novel DnaJ chaperone proteins CG5001 and P58IPK regulate the pathogenicity of Huntington's disease related aggregates.Scientific reports · 2024Article
- Biomolecular condensates and disease pathogenesis.Science China. Life sciences · 2024Review
- Long way up: rethink diseases in light of phase separation and phase transition.Protein & cell · 2024Review
- Physiological and pathological effects of phase separation in the central nervous system.Journal of molecular medicine (Berlin, Germany) · 2024Review
- The Role of Liquid-Liquid Phase Separation in the Accumulation of Pathological Proteins: New Perspectives on the Mechanism of Neurodegenerative Diseases.Aging and disease · 2024Review
- Rational optimization of a transcription factor activation domain inhibitor.Nature structural & molecular biology · 2023Article
- Article
- Protein nanocondensates: the next frontier.Biophysical reviews · 2023Review
- Phase Transitions of Associative Biomacromolecules.Chemical reviews · 2023Review
16 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Huntingtin N-terminal fragments (Htt-NTFs) with expanded polyglutamine tracts form a range of neurotoxic aggregates that are associated with Huntington's disease. Here, we show that aggregation of Htt-NTFs, irrespective of polyglutamine length, yields at least three phases (designated M, S, and F) that are delineated by sharp concentration thresholds and distinct aggregate sizes and morphologies. We found that monomers and oligomers make up the soluble M phase, ∼25-nm spheres dominate in the soluble S phase, and long, linear fibrils make up the insoluble F phase. Previous studies showed that profilin, an abundant cellular protein, reduces Htt-NTF aggregation and toxicity in cells. We confirm that profilin achieves its cellular effects through direct binding to the C-terminal proline-rich region of Htt-NTFs. We show that profilin preferentially binds to Htt-NTF M-phase species and destabilizes aggregation and phase separation by shifting the concentration boundaries for phase separation to higher values through a process known as polyphasic linkage. Our experiments, aided by coarse-grained computer simulations and theoretical analysis, suggest that preferential binding of profilin to the M-phase species of Htt-NTFs is enhanced through a combination of specific interactions between profilin and polyproline segments and auxiliary interactions between profilin and polyglutamine tracts. Polyphasic linkage may be a general strategy that cells utilize to regulate phase behavior of aggregation-prone proteins. Accordingly, detailed knowledge of phase behavior and an understanding of how ligands modulate phase boundaries may pave the way for developing new therapeutics against a variety of aggregation-prone proteins.
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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.