Molecular interactions underlying liquid-liquid phase separation of the FUS low-complexity domain
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. Furthermore, 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/sp2, 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.
- Authors:
-
[1];
[2];
[5];
[2];
[1]
- Brown Univ., Providence, RI (United States)
- Lehigh Univ., Bethlehem, PA (United States)
- LUT Univ., Lappeenranta (Finland); Max Planck Inst. for Polymer Research, Mainz (Germany)
- Lehigh Univ., Bethlehem, PA (United States); Princeton Univ., NJ (United States)
- Max Planck Inst. for Polymer Research, Mainz (Germany); Univ. of Texas, Austin, TX (United States)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC); Lehigh Univ., Bethlehem, PA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Science Foundation (NSF); National Institutes of Health (NIH); German Research Foundation (DFG); Human Frontier Science Program; Marie Curie Foundation
- OSTI Identifier:
- 1577559
- Grant/Contract Number:
- AC02-05CH11231; SC0013979; R01GM118530; RGP0045/2018; NSF 1845734; 1644760; PA-252611-1; CIG322284; MCB-120014
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Structural & Molecular Biology
- Additional Journal Information:
- Journal Volume: 26; Journal Issue: 7; Journal ID: ISSN 1545-9993
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; Intrinsically disordered proteins; NMR spectroscopy; solution-state NMR
Citation Formats
Murthy, Anastasia C., Dignon, Gregory L., Kan, Yelena, Zerze, Gül H., Parekh, Sapun H., Mittal, Jeetain, and Fawzi, Nicolas L. Molecular interactions underlying liquid-liquid phase separation of the FUS low-complexity domain. United States: N. p., 2019.
Web. doi:10.1038/s41594-019-0250-x.
Murthy, Anastasia C., Dignon, Gregory L., Kan, Yelena, Zerze, Gül H., Parekh, Sapun H., Mittal, Jeetain, & Fawzi, Nicolas L. Molecular interactions underlying liquid-liquid phase separation of the FUS low-complexity domain. United States. https://doi.org/10.1038/s41594-019-0250-x
Murthy, Anastasia C., Dignon, Gregory L., Kan, Yelena, Zerze, Gül H., Parekh, Sapun H., Mittal, Jeetain, and Fawzi, Nicolas L. Mon .
"Molecular interactions underlying liquid-liquid phase separation of the FUS low-complexity domain". United States. https://doi.org/10.1038/s41594-019-0250-x. https://www.osti.gov/servlets/purl/1577559.
@article{osti_1577559,
title = {Molecular interactions underlying liquid-liquid phase separation of the FUS low-complexity domain},
author = {Murthy, Anastasia C. and Dignon, Gregory L. and Kan, Yelena and Zerze, Gül H. and Parekh, Sapun H. and Mittal, Jeetain and Fawzi, Nicolas L.},
abstractNote = {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. Furthermore, 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/sp2, 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.},
doi = {10.1038/s41594-019-0250-x},
journal = {Nature Structural & Molecular Biology},
number = 7,
volume = 26,
place = {United States},
year = {Mon Jul 01 00:00:00 EDT 2019},
month = {Mon Jul 01 00:00:00 EDT 2019}
}
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Phase separation in biology; functional organization of a higher order
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Molecular Determinants and Genetic Modifiers of Aggregation and Toxicity for the ALS Disease Protein FUS/TLS
journal, April 2011
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Tau protein liquid–liquid phase separation can initiate tau aggregation
journal, February 2018
- Wegmann, Susanne; Eftekharzadeh, Bahareh; Tepper, Katharina
- The EMBO Journal, Vol. 37, Issue 7
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