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Cited by 698RNA Research and SplicingAmyotrophic Lateral Sclerosis ResearchProtein Structure and Dynamics

Molecular interactions underlying liquid‐liquid phase separation of the FUS low‐complexity domain

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Murthy, Anastasia C., Dignon, Gregory L., Kan, Yelena, Zerze, Gül H., Parekh, Sapun H., Mittal, Jeetain, Fawzi, Nicolas L.·2019·Nature Structural & Molecular Biology
DOI 10.1038/s41594-019-0250-xPMC PMC6613800
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Abstract

The low-complexity domain of the RNA-binding protein FUS (FUS LC) mediates liquid-liquid phase separation (LLPS), but the interactions between the repetitive SYGQ-rich sequence of FUS LC that stabilize the liquid phase are not known in detail. By combining NMR and Raman spectroscopy, mutagenesis, and molecular simulation, we demonstrate that heterogeneous interactions involving all residue types underlie LLPS of human FUS LC. We find no evidence that FUS LC adopts conformations with traditional secondary structure elements in the condensed phase; rather, it maintains conformational heterogeneity. We show that hydrogen bonding, π/sp 2, and hydrophobic interactions all contribute to stabilizing LLPS of FUS LC. In addition to contributions from tyrosine residues, we find that glutamine residues also participate in contacts leading to LLPS of FUS LC. These results support a model in which FUS LC forms dynamic, multivalent interactions via multiple residue types and remains disordered in the densely packed liquid phase.

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Sorted by citations

Authors
Murthy, A. C., Dignon, G. L., Kan, Y., Zerze, G. H., Parekh, S. H., Mittal, J., & Fawzi, N. L.
Affiliations
  • Brown University (US)
  • Lehigh University (US)
  • Max Planck Institute for Polymer Research (DE)
Corresponding author
  • Mittal, Jeetain
  • Fawzi, Nicolas L.
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
Springer Science and Business Media LLC
Published
2019-07
Volume
26
Issue
7
Pages
637-648
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
DOI
10.1038/s41594-019-0250-x
PMC
PMC6613800
OpenAlex
W2953933961
Cited by
698
References
1
Citations by year
2026: 100 · 2025: 122 · 2024: 113 · 2023: 94 · 2022: 96 · 2021: 104 · 2020: 59 · 2019: 10
FWCI
22.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
  • National Science Foundation (TG‐MCB‐120014, DEAC02-05CH11231, 1845734, MCB-120014, 1644760)
  • U.S. Department of Energy (-AC02-05CH11231, 05CH11231, DE AC02 05CH11231, DESC0013979, DE-AC02-)
  • Brown University
  • European Commission (322284)
  • Deutsche Forschungsgemeinschaft (DE-AC02-05CH11231)
  • Office of Science (DEAC02–05CH11231, AC02-05CH11231, DE-AC02)
  • National Institute of General Medical Sciences (DE-AC02-05CH11231, 1644760, T32GM007601, R01GM118530)
  • Basic Energy Sciences (DE-AC02, DE-AC02-05CH11231., AC02–05CH11231)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
liquid-liquid phase separation, RNA-binding proteins, intrinsically disordered proteins, multivalent interactions, hydrogen bonding, hydrophobic interactions, tyrosine residues, glutamine residues, conformational heterogeneity, amyotrophic lateral sclerosis
MeSH terms
Protein Domains, Humans, Hydrogen Bonding, Models, Molecular, Protein Conformation, Protein Structure, Secondary, RNA-Binding Protein FUS, Phase Transition, Hydrophobic and Hydrophilic Interactions, Intrinsically Disordered Proteins

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