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Fused in sarcoma undergoes cold denaturation: Implications on phase separation
Open accessPreprint — published as 10.1002/pro.4521 · Paper page
Abstract
The mediation of fused in sarcoma (FUS) protein liquid-liquid phase separation (LLPS) is generally attributed to the low-complexity and disordered domains, while the role of its folded domains remains unknown. In this work we questioned the role of the folded domains on the full-length (FL) FUS LLPS and studied the influence of several metabolites, ions and overall conditions on the LLPS process using turbidity assays, differential interference contrast microscopy and nuclear magnetic resonance spectroscopy. We demonstrate that FL FUS LLPS is highly responsive to the surrounding conditions, and that overall intrinsic disorder is crucial for LLPS. To promote such disorder, we reveal that the FUS RNA-recognition domain (RRM) and the zinc-finger motif (ZnF) undergo cold denaturation above 0ºC, at a temperature that is determined by the conformational stability of the ZnF domain. We hypothesize that, in cold shock conditions, cold denaturation might provide a pathway that exposes additional residues to promote FUS self-assembly. Such findings mark the first evidence that FUS globular domains may have an active role in stress granule formation in cold stress.
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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
- openRxiv
- Published
- 2022-02-10
- Volume
- 32
- Issue
- 1
- Pages
- e4521-e4521
- ISSN
- 0961-8368 (ISSN-L)
- 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
- cc-by-nc-nd
- 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
- Fundación BBVA (MCIN/ AEI /10.13039/501100011033, BBM‐TRA‐0203)
- Ministerio de Ciencia e Innovación (PID‐2019‐109306RB‐I00, MCIN/AEI/10.13039/501100011033,, PID‐2019‐109276RA‐I00, RYC2018‐026042‐I)
- Banco Bilbao Vizcaya Argentaria (MCIN/AEI/10.13039/501100011033)
- Applied Molecular Biosciences Unit (LA/P/0140/2020, UIDP/04378/2020, UIDB04378/2020)
- Fundação para a Ciência e a Tecnologia (PINFRA/22161/2016, COMPETE, 22161/2016, MCIN/AEI/10.13039/501100011033/, UIDB/04378/2020, COMPETE_2020, UIDP/04378/2020, PD/BD/148028/2019, ROTEIRO/0031/2013, 10.13039/501100011033, ROTEIRO/0031/2013—PINFRA/22161/2016, LA/P/0140/2020)
- Agencia Estatal de Investigación (AEI//10.13039/501100011033/, 501100011033, by MCIN/AEI/10.13039/501100011033, 10.13039/501100011033, MCIN/AEI/10.13039/501 100 011 033, 13039, .13039/501100011033, MCIN / AEI/10, 10.13039, LA/P/0140/2020, AEI/10)
- European Social Fund (UIDB/04378/2020, COMPETE 2020, LA/P/0140/2020, MCIN/AEI/10.13039/ 501100011033, 501100011033, UIDP/04378/2020, AEI/10.13039/501100011033)
- 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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