Fibril formation and ordering of disordered FUS LC driven by hydrophobic interactions

Maltseva, Daria; Chatterjee, Sayantan; Yu, Chia‐Li; Brzezinski, Mateusz; Nagata, Yuki; Gonella, Grazia; Murthy, Anastasia C.; Stachowiak, Jeanne C.; Fawzi, Nicolas L.; Parekh, Sapun H.; Bonn, Mischa

doi:10.1038/s41557-023-01221-1

Cited by 18 publications

(15 citation statements)

References 78 publications

(84 reference statements)

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“…Surprisingly, we found that the aromatic C–H peaks are all negative, which starkly contrasts the variety of the molecular orientation of the studied benzene derivatives. Note that the negative ∼3050–3100 cm –1 Im(χ YYZ (2) ) peak appears not only for the pure organic solvents of the benzene derivatives but also for benzene derivatives in water ,,, and proteins in water, ,,, indicating that the negative peak is rather universal, independent of the orientation of molecules. Our result clearly suggests a large quadrupole contribution in the aromatic C–H stretching mode.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast, if a signal is dominated by the quadrupole contribution, the information on the orientation of the interfacial molecule cannot be accessed. − The origin of the HD-SFG signal of benzene has been extensively discussed in the literature because the Im(χ (2) ) signal has an aromatic C–H stretching peak despite benzene having no apparent transition dipole moment. − In contrast, the origin of the aromatic C–H mode of benzene derivatives in the Im(χ (2) ) response has not been explored, presumably because of the apparent dipole moment (see Figure ). However, the data published so far commonly show a negative aromatic C–H stretching peak, ,,− questioning whether the benzene derivative aromatic C–H stretching mode reflects the molecular orientation.…”

Section: Introductionmentioning

confidence: 99%

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Does the Sum-Frequency Generation Signal of Aromatic C–H Vibrations Reflect Molecular Orientation?

Matsumura

et al. 2023

J. Phys. Chem. B

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Organic molecules with aromatic groups at the aqueous interfaces play a central role in atmospheric chemistry, green chemistry, and on-water synthesis. Insights into the organization of interfacial organic molecules can be obtained using surface-specific vibrational sum-frequency generation (SFG) spectroscopy. However, the origin of the aromatic C−H stretching mode peak is unknown, prohibiting us from connecting the SFG signal to the interfacial molecular structure. Here, we explore the origin of the aromatic C−H stretching response by heterodyne-detected SFG (HD-SFG) at the liquid/vapor interface of benzene derivatives and find that, irrespective of the molecular orientation, the sign of the aromatic C−H stretching signals is negative for all the studied solvents. Together with density functional theory (DFT) calculations, we reveal that the interfacial quadrupole contribution dominates, even for the symmetry-broken benzene derivatives, although the dipole contribution is non-negligible. We propose a simple evaluation of the molecular orientation based on the aromatic C−H peak area.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Does the Sum-Frequency Generation Signal of Aromatic C–H Vibrations Reflect Molecular Orientation?

Matsumura

et al. 2023

J. Phys. Chem. B

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“…To further investigate how the identity of polar residues affects LST, we tested the ability of FUS variants to aggregate as a function of time. We used both quiescent conditions and shaking that generates shear and disruption at phase interfaces that can nucleate aggregation 72,73 , monitoring the onset and morphology of the aggregation over a 24 hour time course using DIC microscopy (Fig. 5a, left).…”

Section: Liquid-to-solid Transition Is Dependent On Non-tyrosine Pola...mentioning

confidence: 99%

Expanding the molecular grammar of polar residues and arginine in FUS prion-like domain phase separation and aggregation

Wake,

Weng,

Zheng

et al. 2024

Preprint

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A molecular grammar governing low-complexity prion-like domains phase separation (PS) has been proposed based on mutagenesis experiments that identified tyrosine and arginine as primary drivers of phase separation via aromatic-aromatic and aromatic-arginine interactions. Here we show that additional residues make direct favorable contacts that contribute to phase separation, highlighting the need to account for these contributions in PS theories and models. We find that tyrosine and arginine make important contacts beyond only tyrosine-tyrosine and tyrosine-arginine, including arginine-arginine contacts. Among polar residues, glutamine in particular contributes to phase separation with sequence/position-specificity, making contacts with both tyrosine and arginine as well as other residues, both before phase separation and in condensed phases. For glycine, its flexibility, not its small solvation volume, favors phase separation by allowing favorable contacts between other residues and inhibits the liquid-to-solid (LST) transition. Polar residue types also make sequence-specific contributions to aggregation that go beyond simple rules, which for serine positions is linked to formation of an amyloid-core structure by the FUS low-complexity domain. Hence, here we propose a revised molecular grammar expanding the role of arginine and polar residues in prion-like domain protein phase separation and aggregation.

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“…Fused in sarcoma (FUS) is an RNA/DNA binding protein and is associated with some intracellular processes such as transcription regulation, RNA splicing, and mRNA transportation. , Many studies have shown that FUS protein undergoes phase separation, a transition from the dispersed state to droplets, gel, or fibrillary gel as FUS contains the low complexity domain (LCD), − which tends to lead to multivalent interactions of the proteins. The abnormal phase separation of FUS is involved with the development of neurodegenerative diseases such as familial amyotrophic lateral sclerosis (ALS-FUS). , In addition, FUS and two other proteins of the common protein family (FET family) are codeposited in the cytoplasm of a subset of patients with frontotemporal lobar degeneration (FTLD-FUS) .…”

Section: Introductionmentioning

confidence: 99%

Study on Phase Separation of Fused in Sarcoma by Fluorescence Correlation Spectroscopy

Yu,

Liu,

Huang

et al. 2023

Langmuir

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Liquid−liquid phase separation (LLPS) of fused in sarcoma (FUS) has emerged as a fundamental principle underpinning cellular function and malfunction. However, we know little about the FUS phase transition process from individual molecules to nanoscale condensates, which plays important roles in neurodegenerative diseases. Here, we propose the fluorescence correlation spectroscopy (FCS) method to quantitatively study the phase separation process of FUS protein with the fluorescent tag-enhanced green fluorescent protein (EGFP), from individual molecules to nanoscale condensates. The characteristic diffusion time (τ D ) of the protein condensates can be obtained from the FCS curve, which increases with the growth of the protein hydration radius. The bigger the τ D value of the protein condensates, the larger the condensates formed by the phase separation of FUS. By this method, we discovered that the critical concentration for FUS to phase separation was 20 nM. We then plotted FUS phase diagrams based on τ D under different concentrations of NaCl and found that both low-salt and high-salt concentrations tended to promote FUS-EGFP phase separation. Our results showed that ATP has a good inhibitory effect on FUS phase separation, and its inhibition constant IC 50 was 3.2 mM. Finally, we evaluated the inhibition efficiency of single-stranded DNA sequences (ssDNA) on FUS phase separation and demonstrated that ssDNA containing three copies of TCCCCGT had relatively strong inhibition efficiency. In summary, our work provides detailed insight into the FUS phase transition process from individual molecules to nanoscale condensates at nanomolar concentrations and can be exploited for drug screening of neurodegenerative diseases.

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Fibril formation and ordering of disordered FUS LC driven by hydrophobic interactions

Cited by 18 publications

References 78 publications

Does the Sum-Frequency Generation Signal of Aromatic C–H Vibrations Reflect Molecular Orientation?

Does the Sum-Frequency Generation Signal of Aromatic C–H Vibrations Reflect Molecular Orientation?

Expanding the molecular grammar of polar residues and arginine in FUS prion-like domain phase separation and aggregation

Study on Phase Separation of Fused in Sarcoma by Fluorescence Correlation Spectroscopy

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