Composition-based prediction and rational manipulation of prion-like domain recruitment to stress granules
| Autor: | Eric D. Ross, Andrew K. Lamb, Matthew H. Baer, Kacy R. Paul, Jenifer E. Shattuck, Sean M. Cascarina, Amy E. Boncella, Anastasia Fomicheva |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Prions
Saccharomyces cerevisiae yeast stress granule Cytoplasmic Granules Biochemistry Prion Proteins prion Stress (mechanics) 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Stress granule Protein Domains Sequence Analysis Protein Stress Physiological Aromatic amino acids Prion protein Sodium Azide Heat-Shock Proteins 030304 developmental biology Sequence (medicine) prion-like Base Composition 0303 health sciences Multidisciplinary Colocalization Neurodegenerative Diseases Biological Sciences Composition (combinatorics) Yeast Cell biology chemistry Mutation 030217 neurology & neurosurgery |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Many RNA-binding proteins contain aggregation-prone prion-like domains (PrLDs), and mutations in several of these have been linked to degenerative diseases. Additionally, many of these proteins are associated with stress granules, which are membraneless organelles that form under stress, in part through reversible protein assembly. Although the mechanisms of stress granule assembly are unclear, PrLDs can play a role in this process. In order to further understand how PrLDs respond to stress, we analyzed the assembly propensities of a selection of different PrLDs from yeast. We find that many PrLDs are efficiently recruited to stress-induced assemblies and that this recruitment is predominantly dependent on the amino acid composition of the PrLDs. Mutations in a number of stress granule-associated proteins have been linked to various neurodegenerative diseases. Several of these mutations are found in aggregation-prone prion-like domains (PrLDs) within these proteins. In this work, we examine the sequence features governing PrLD localization to stress granules upon stress. We demonstrate that many yeast PrLDs are sufficient for stress-induced assembly into microscopically visible foci that colocalize with stress granule markers. Additionally, compositional biases exist among PrLDs that assemble upon stress, and these biases are consistent across different stressors. Using these biases, we have developed a composition-based prediction method that accurately predicts PrLD assembly into foci upon heat shock. We show that compositional changes alter PrLD assembly behavior in a predictable manner, while scrambling primary sequence has little effect on PrLD assembly and recruitment to stress granules. Furthermore, we were able to design synthetic PrLDs that were efficiently recruited to stress granules, and found that aromatic amino acids, which have previously been linked to PrLD phase separation, were dispensable for this recruitment. These results highlight the flexible sequence requirements for stress granule recruitment and suggest that PrLD localization to stress granules is driven primarily by amino acid composition, rather than primary sequence. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|