The mutational landscape of a prion-like domain
By Benedetta Bolognesi, André J. Faure, Mireia Seuma, Joern M Schmiedel, G. Tartaglia, Ben Lehner. 2019
144 citations recorded by the source corpus.
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. TDP43 aggregates are a hallmark of amyotrophic lateral sclerosis. By using deep mutagenesis to measure the toxicity of more than 50,000 mutations in the prion domain of TDP43, the authors conclude that mutations that increase toxicity promote formation of liquid-like condensates, while aggregation of TDP43 is protective for the cell.
Subfields: Molecular Biology, Neurology
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Citations in the corpus
- Evolutionary context-integrated deep sequence modeling for protein engineering (2020, methodology): “We collected the fitness measurements of both single and double mutants of six proteins from previous DMS studies [37,49–53] .”
- Determining protein structures using deep mutagenesis (2019, background): “Finally, and perhaps most interestingly, DMS allows the structures of macromolecules to be studied in vivo in the cell 60 .”