Single-molecule FRET unmasks structural subpopulations and crucial molecular events during FUS low-complexity domain phase separation

Ashish Joshi, Anuja Walimbe, Anamika Avni, Sandeep K. Rai, Lisha Arora, Snehasis Sarkar and Samrat Mukhopadhyay ()
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Ashish Joshi: Indian Institute of Science Education and Research (IISER) Mohali
Anuja Walimbe: Indian Institute of Science Education and Research (IISER) Mohali
Anamika Avni: Indian Institute of Science Education and Research (IISER) Mohali
Sandeep K. Rai: Indian Institute of Science Education and Research (IISER) Mohali
Lisha Arora: Indian Institute of Science Education and Research (IISER) Mohali
Snehasis Sarkar: Indian Institute of Science Education and Research (IISER) Mohali
Samrat Mukhopadhyay: Indian Institute of Science Education and Research (IISER) Mohali

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Biomolecular condensates formed via phase separation of proteins and nucleic acids are thought to be associated with a wide range of cellular functions and dysfunctions. We dissect critical molecular events associated with phase separation of an intrinsically disordered prion-like low-complexity domain of Fused in Sarcoma by performing single-molecule studies permitting us to access the wealth of molecular information that is skewed in conventional ensemble experiments. Our single-molecule FRET experiments reveal the coexistence of two conformationally distinct subpopulations in the monomeric form. Single-droplet single-molecule FRET studies coupled with fluorescence correlation spectroscopy, picosecond time-resolved fluorescence anisotropy, and vibrational Raman spectroscopy indicate that structural unwinding switches intramolecular interactions into intermolecular contacts allowing the formation of a dynamic network within condensates. A disease-related mutation introduces enhanced structural plasticity engendering greater interchain interactions that can accelerate pathological aggregation. Our findings provide key mechanistic underpinnings of sequence-encoded dynamically-controlled structural unzipping resulting in biological phase separation.

Date: 2023
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DOI: 10.1038/s41467-023-43225-y

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