The mutational landscape of a prion-like domain

Benedetta Bolognesi (), Andre J. Faure, Mireia Seuma, Jörn M. Schmiedel, Gian Gaetano Tartaglia and Ben Lehner ()
Additional contact information
Benedetta Bolognesi: Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
Andre J. Faure: Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
Mireia Seuma: Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
Jörn M. Schmiedel: Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
Gian Gaetano Tartaglia: Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
Ben Lehner: Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (6)

Downloads: (external link)
https://www.nature.com/articles/s41467-019-12101-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12101-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-12101-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().