ArticleNature communications2019
The mutational landscape of a prion-like domain.
Article in Nature communications, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 113 papers.
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Who cites it
113 citing papers in PubMed.
- Interpretable biophysical neural networks of transcriptional activation domains separate roles of protein abundance and coactivator binding.Cell systems · 2026Article
- Combining multiplexed functional data to improve variant classification.Genome medicine · 2026Article
- Molecular dynamics simulations of intrinsically disordered protein regions enable biophysical interpretation of variant-effect predictors.HGG advances · 2026Article
- High-throughput screening approach identifies substrate-selective Hsp104 variants that counter amyloid seeding with diminished off-target effects.Molecular cell · 2026Article
- Review
- FuzDrop: sequence-based prediction of the propensity of proteins for liquid-liquid phase separation and aggregation.Nature protocols · 2026Review
- Mutational Scanning of α-Synuclein using a Clickable Protein Tag Reveals Determinants of Membrane-Induced Aggregation.bioRxiv : the preprint server for biology · 2026Article
- TDP43 and hnRNP K Regulate Alternative Splicing of DNAJC5.Cell biology international · 2026Article
- Compressing the collective knowledge of ESM into a single protein language model.Nature methods · 2026Article
- Massively parallel quantification of mutational impact on IAPP amyloid formation.Nature communications · 2026Article
- Article
- Sequence and chemical specificity define the functional landscape of intrinsically disordered regions.Nature cell biology · 2026Article
- Concentration-dependent mutational scanning probes the cellular folding landscape of α-synuclein in yeast.Protein science : a publication of the Protein Society · 2026Article
- Understanding liquid-liquid phase separation through TDP-43: fundamental principles, subcellular compartmentalisation, and role of solid inclusion formation.Genome biology · 2026Review
- Scp160 deletion suppresses TDP-43 aggregation and toxicity inMicrobial cell (Graz, Austria) · 2026Article
- Beyond motor neurons: peripheral TDP-43 pathology in skeletal muscle and intramuscular nerves in amyotrophic lateral sclerosis.Brain communications · 2026Review
- Concentration-Dependent Mutational Scanning Probes the Cellular Folding Landscape of α-Synuclein in Yeast.bioRxiv : the preprint server for biology · 2025Article
- A DNA language model based on multispecies alignment predicts the effects of genome-wide variants.Nature biotechnology · 2025Article
- Structural details of helix-mediated multimerization of the conserved region of TDP-43 C-terminal domain.Nature communications · 2025Article
- MaveMD: A functional data resource for genomic medicine.medRxiv : the preprint server for health sciences · 2025Article
53 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
6 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Insoluble protein aggregates are the hallmarks of many neurodegenerative diseases. For example, aggregates of TDP-43 occur in nearly all cases of amyotrophic lateral sclerosis (ALS). However, whether aggregates cause cellular toxicity is still not clear, even in simpler cellular systems. We reasoned that deep mutagenesis might be a powerful approach to disentangle the relationship between aggregation and toxicity. We generated >50,000 mutations in the prion-like domain (PRD) of TDP-43 and quantified their toxicity in yeast cells. Surprisingly, mutations that increase hydrophobicity and aggregation strongly decrease toxicity. In contrast, toxic variants promote the formation of dynamic liquid-like condensates. Mutations have their strongest effects in a hotspot that genetic interactions reveal to be structured in vivo, illustrating how mutagenesis can probe the in vivo structures of unstructured proteins. Our results show that aggregation of TDP-43 is not harmful but protects cells, most likely by titrating the protein away from a toxic liquid-like phase.
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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.