Valence and patterning of aromatic residues determine the phase behavior of prion-like domains
Open accessAbstract
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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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”
From AlphaFold and Implications for Intrinsically Disordered Proteins (2021) · cites this paper as [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”
From AlphaFold and Implications for Intrinsically Disordered Proteins (2021) · cites this paper as [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”
From AlphaFold and Implications for Intrinsically Disordered Proteins (2021) · cites this paper as [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
- ORCID
- Venue
- Science
- Published
- 2020-02-07
- Volume
- 367
- Issue
- 6478
- Pages
- 694-699
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7297187
- 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
- green
- europepmc.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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