ArticleStructure (London, England : 1993)2019
ALS-Linked Mutations Affect UBQLN2 Oligomerization and Phase Separation in a Position- and Amino Acid-Dependent Manner.
Article in Structure (London, England : 1993), 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 62 papers.
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62 citing papers in PubMed, 99 citations in OpenAlex.
- ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties.bioRxiv : the preprint server for biology · 2026Article
- Programmable Multiphasic Condensates Formed via Evaporation-Induced Phase Separation of Minimal Peptide Model.Advanced materials (Deerfield Beach, Fla.) · 2026Article
- STI1 domains coordinate partitioning of UBQLN2 into stress-induced condensates.bioRxiv : the preprint server for biology · 2026Article
- ALS mutations disrupt self-association between the ubiquilin STI1 hydrophobic groove and internal placeholder sequences.The EMBO journal · 2026Article
- Ubiquilin-2 liquid droplets catalyze α-synuclein fibril formation.The EMBO journal · 2025Article
- Correlated Segments of Intrinsically Disordered Proteins as Drivers of Homotypic Phase Separation.JACS Au · 2025Article
- UBQLN2 in neurodegenerative disease: mechanistic insights and emerging therapeutic potential.Biochemical Society transactions · 2025Review
- Stress granules attenuate protein nanoparticle induced osmotic imbalance via membrane potential restoration.Scientific reports · 2025Article
- Single-point mutations in disordered proteins: Linking sequence, ensemble, and function.Current opinion in structural biology · 2025Review
- Molecular determinants of condensate composition.Molecular cell · 2025Review
- Adenosine diphosphate-ribosylation greatly affects proteins function: a focus on neurodegenerative diseases.Frontiers in aging neuroscience · 2025Review
- Cellular Prion Protein Conformational Shift after Liquid-Liquid Phase Separation Regulated by a Polymeric Antagonist and Mutations.Journal of the American Chemical Society · 2024Article
- Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia.Brain : a journal of neurology · 2024Article
- Phase separation of polyubiquitinated proteins in UBQLN2 condensates controls substrate fate.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Phase separation of polyubiquitinated proteins in UBQLN2 condensates controls substrate fate.bioRxiv : the preprint server for biology · 2024Article
- Short disordered termini and proline-rich domain are major regulators of UBQLN1/2/4 phase separation.Biophysical journal · 2024Article
- Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia.Brain pathology (Zurich, Switzerland) · 2024Article
- Pathogenic mutations in UBQLN2 exhibit diverse aggregation propensity and neurotoxicity.Scientific reports · 2024Article
- Phase Separation as a Driver of Stem Cell Organization and Function during Development.Journal of developmental biology · 2023Review
- Sequence variations of phase-separating proteins and resources for studying biomolecular condensates.Acta biochimica et biophysica Sinica · 2023Review
2 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Proteasomal shuttle factor UBQLN2 is recruited to stress granules and undergoes liquid-liquid phase separation (LLPS) into protein-containing droplets. Mutations to UBQLN2 have recently been shown to cause dominant X-linked inheritance of amyotrophic lateral sclerosis (ALS) and ALS/dementia. Interestingly, most of these UBQLN2 mutations reside in its proline-rich (Pxx) region, an important modulator of LLPS. Here, we demonstrated that ALS-linked Pxx mutations differentially affect UBQLN2 LLPS, depending on both amino acid substitution and sequence position. Using size-exclusion chromatography, analytical ultracentrifugation, microscopy, and NMR spectroscopy, we determined that those Pxx mutants that enhanced UBQLN2 oligomerization decreased saturation concentrations needed for LLPS and promoted solid-like and viscoelastic morphological changes to UBQLN2 liquid assemblies. Ubiquitin disassembled all LLPS-induced mutant UBQLN2 aggregates. We postulate that the changes in physical properties caused by ALS-linked Pxx mutations modify UBQLN2 behavior in vivo, possibly contributing to aberrant stress granule morphology and dynamics, leading to formation of inclusions, pathological characteristics of ALS.
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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.