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Fused in sarcoma undergoes cold denaturation: Implications for phase separation
Open accessPublished version of a preprint
Abstract
The mediation of liquid–liquid phase separation (LLPS) for fused in sarcoma (FUS) protein is generally attributed to the low‐complexity, disordered domains and is enhanced at low temperature. The role of FUS folded domains on the LLPS process remains relatively unknown since most studies are mainly based on fragmented FUS domains. Here, we investigate the effect of metabolites on full‐length (FL) FUS LLPS using turbidity assays and differential interference contrast (DIC) microscopy, and explore the behavior of the folded domains by nuclear magnetic resonance (NMR) spectroscopy. FL FUS LLPS is maximal at low concentrations of glucose and glutamate, moderate concentrations of NaCl, Zn 2+ , and Ca 2+ and at the isoelectric pH. The FUS RNA recognition motif (RRM) and zinc‐finger (ZnF) domains are found to undergo cold denaturation above 0°C at a temperature that is determined by the conformational stability of the ZnF domain. Cold unfolding exposes buried nonpolar residues that can participate in LLPS‐promoting hydrophobic interactions. Therefore, these findings constitute the first evidence that FUS globular domains may have an active role in LLPS under cold stress conditions and in the assembly of stress granules, providing further insight into the environmental regulation of LLPS.
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Metadata
- Authors
- Félix, S. S., Laurents, D. V., Oroz, J., & Cabrita, E. J.
- Affiliations
- Consejo Superior de Investigaciones Científicas (ES)
- Universidade Nova de Lisboa (PT)
- Corresponding author
- Oroz, Javier
- Cabrita, Eurico J.
- Venue
- Protein Science
- Publisher
- Wiley
- Published
- 2022-12-19
- Volume
- 32
- Issue
- 1
- Pages
- e4521-e4521
- ISSN
- 0961-8368 (ISSN-L)
- 1469-896X
- PMC
- PMC9793971
- OpenAlex
- W4310572064
- Cited by
- 12
- References
- 1
- Citations by year
- 2025: 5 · 2024: 2 · 2023: 4 · 2022: 1
- FWCI
- 1.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Protein Science (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by-nc-nd)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Funders
- Foundation for Science and Technology (LA/P/0140/2020, PD/BD/148028/2019, ROTEIRO/0031/2013‐PINFRA/22161/2016, UIDP/04378/2020, UIDB/04378/2020)
- BBVA Foundation (BBM_TRA_0203)
- Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033, PID‐2019‐109276RA‐I00, PID‐2019‐109306RB‐I00, RYC2018‐026042‐I)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- 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
- Keywords
- FUS protein, liquid-liquid phase separation, cold denaturation, RNA recognition motif, zinc finger, stress granules, low-complexity domains, hydrophobic interactions, protein conformational stability
- MeSH terms
- Protein Domains, Humans, Magnetic Resonance Spectroscopy, Sarcoma, Temperature, Zinc Fingers
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