Cited by 1,147RNA Research and SplicingProtein Structure and DynamicsRNA and protein synthesis mechanisms

Valence and patterning of aromatic residues determine the phase behavior of prion-like domains

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Martin, Erik W., Holehouse, Alex S., Peran, Ivan, Farag, Mina, Incicco, J. Jeremias, Bremer, Anne, Grace, Christy R., Soranno, Andrea +2 more·2020·Science

Abstract

Prion-like domains (PLDs) can drive liquid-liquid phase separation (LLPS) in cells. Using an integrative biophysical approach that includes nuclear magnetic resonance spectroscopy, small-angle x-ray scattering, and multiscale simulations, we have uncovered sequence features that determine the overall phase behavior of PLDs. We show that the numbers (valence) of aromatic residues in PLDs determine the extent of temperature-dependent compaction of individual molecules in dilute solutions. The valence of aromatic residues also determines full binodals that quantify concentrations of PLDs within coexisting dilute and dense phases as a function of temperature. We also show that uniform patterning of aromatic residues is a sequence feature that promotes LLPS while inhibiting aggregation. Our findings lead to the development of a numerical stickers-and-spacers model that enables predictions of full binodals of PLDs from their sequences.

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Crossref · 10.1126/science.aaw8653

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  • Integrating SAXS and NMR measurements with simulations suggests that the ensemble of conformations of A1-LCD fluctuates among locally compact regions, globally compact conformations, and expanded conformations.

    “Integrating SAXS and NMR measurements with simulations, suggests that the ensemble of conformations fluctuate among locally compact regions, globally compact conformations, and expanded conformations.88”
  • These conformational features of A1-LCD are driven by the distributed network of contacts formed between pairs of sequence-proximal or distal aromatic residues and influenced or diluted by the spacer regions that are interspersed between aromatic residues (stickers).

    “These conformational features are driven by the distributed network of contacts formed between pairs of sequenceproximal or distal aromatic residues and influenced or diluted by the spacer regions that are interspersed between aromatic residues (stickers).88”
  • Detailed atomistic descriptions of conformational ensembles enabled the development of a coarse-grained stickers-and-spacers model for simulations of A1-LCD phase behavior.

    “Importantly, the detailed atomistic descriptions of conformational ensembles enabled the development of a coarse-grained stickers-and-spacers model for simulations of A1-LCD phase behavior.88”

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Authors
Martin, E. W., Holehouse, A. S., Peran, I., Farag, M., Incicco, J. J., Bremer, A., Grace, C. R., Soranno, A., Pappu, R. V., & Mittag, T.
Affiliations
  • St. Jude Children's Research Hospital (US)
  • Washington University in St. Louis (US)
  • Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Corresponding author
  • Martin, Erik W.
  • Holehouse, Alex S.
  • Peran, Ivan
  • Pappu, Rohit V.
  • Mittag, Tanja
Venue
Science
Published
2020-02-07
Volume
367
Issue
6478
Pages
694-699
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W3005177895
Cited by
1,147
References
67
Citations by year
2026: 184 · 2025: 226 · 2024: 205 · 2023: 168 · 2022: 141 · 2021: 141 · 2020: 79 · 2019: 1 · 2018: 1 · 2017: 1
FWCI
42.88
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Science Foundation (MCB1614766)
  • American Federation for Aging Research
  • St. Jude Children's Research Hospital
  • American Lebanese Syrian Associated Charities
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
Keywords
prion-like domains, liquid-liquid phase separation, aromatic residues, aggregation inhibition, sequence-structure-function relationships
MeSH terms
Protein Domains, Heterogeneous Nuclear Ribonucleoprotein A1, Amino Acid Sequence, Magnetic Resonance Spectroscopy, Phenylalanine, Prions, Tyrosine, X-Ray Diffraction, Phase Transition, Scattering, Small Angle

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