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Natural Selection on the Phase-Separation Properties of FUS during 160 My of Mammalian Evolution


Dasmeh, Pouria; Wagner, Andreas (2021). Natural Selection on the Phase-Separation Properties of FUS during 160 My of Mammalian Evolution. Molecular Biology and Evolution, 38(3):940-951.

Abstract

Protein phase separation can help explain the formation of many nonmembranous organelles. However, we know little about its ability to change in evolution. Here we studied the evolution of the mammalian RNA-binding protein Fused in Sarcoma (FUS), a protein whose prion-like domain (PLD) contributes to the formation of stress granules through liquid–liquid phase separation. Although the PLD evolves three times as rapidly as the remainder of FUS, it harbors absolutely conserved tyrosine residues that are crucial for phase separation. Ancestral reconstruction shows that the phosphorylation sites within the PLD are subject to stabilizing selection. They toggle among a small number of amino acid states. One exception to this pattern is primates, where the number of such phosphosites has increased through positive selection. In addition, we find frequent glutamine to proline changes that help maintain the unstructured state of FUS that is necessary for phase separation. Our work provides evidence that natural selection has stabilized the liquid forming potential of FUS and minimized the propensity of cytotoxic liquid-to-solid phase transitions during 160 My of mammalian evolution.

Abstract

Protein phase separation can help explain the formation of many nonmembranous organelles. However, we know little about its ability to change in evolution. Here we studied the evolution of the mammalian RNA-binding protein Fused in Sarcoma (FUS), a protein whose prion-like domain (PLD) contributes to the formation of stress granules through liquid–liquid phase separation. Although the PLD evolves three times as rapidly as the remainder of FUS, it harbors absolutely conserved tyrosine residues that are crucial for phase separation. Ancestral reconstruction shows that the phosphorylation sites within the PLD are subject to stabilizing selection. They toggle among a small number of amino acid states. One exception to this pattern is primates, where the number of such phosphosites has increased through positive selection. In addition, we find frequent glutamine to proline changes that help maintain the unstructured state of FUS that is necessary for phase separation. Our work provides evidence that natural selection has stabilized the liquid forming potential of FUS and minimized the propensity of cytotoxic liquid-to-solid phase transitions during 160 My of mammalian evolution.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Evolutionary Biology and Environmental Studies
Dewey Decimal Classification:570 Life sciences; biology
590 Animals (Zoology)
Scopus Subject Areas:Life Sciences > Ecology, Evolution, Behavior and Systematics
Life Sciences > Molecular Biology
Life Sciences > Genetics
Uncontrolled Keywords:Genetics, Molecular Biology, Ecology, Evolution, Behavior and Systematics
Language:English
Date:9 March 2021
Deposited On:23 Feb 2022 10:55
Last Modified:26 Feb 2024 02:50
Publisher:Oxford University Press
ISSN:0737-4038
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/molbev/msaa258
PubMed ID:33022038
Project Information:
  • : FunderH2020
  • : Grant ID739874
  • : Project TitleNoiseRobustEvo - Noise and robustness in the evolution of novel protein phenotypes
  • : FunderSNSF
  • : Grant ID31003A_172887
  • : Project TitleRobustness and weakened selection in the adaptive evolution of fluorescent proteins
  • : FunderEvolutionary Biology at the University of Zurich
  • : Grant ID
  • : Project Title
  • Content: Published Version
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)
  • Content: Accepted Version