Composition-based prediction and rational manipulation of prion-like domain recruitment to stress granules.

Autor:	Boncella AE; Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523., Shattuck JE; Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523., Cascarina SM; Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523., Paul KR; Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523., Baer MH; Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523., Fomicheva A; Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523., Lamb AK; Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523., Ross ED; Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, CO 80523 eric.ross@colostate.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Mar 17; Vol. 117 (11), pp. 5826-5835. Date of Electronic Publication: 2020 Mar 03.
DOI:	10.1073/pnas.1912723117
Abstrakt:	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. Competing Interests: The authors declare no competing interest. (Copyright © 2020 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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