Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 26, Issue 7, Pages 637-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41594-019-0250-x
Keywords
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Funding
- NIGMS [R01GM118530]
- Human Frontier Science Program [RGP0045/2018]
- NSF [1845734, TG-MCB-120014]
- NIGMS training grant [T32GM007601]
- NSF graduate fellowship [1644760]
- U.S. Department of Energy (DOE), Office of Science, Basic Energy Sciences (BES), Division of Material Sciences and Engineering [DESC0013979]
- Deutsche Forschungsgemeinschaft (DFG) [PA-252611-1]
- Marie Curie Foundation [CIG322284]
- Office of Science of the U.S. Department of Energy [DE-AC02-05CH11231]
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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, pi/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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