Does liquid–liquid phase separation drive peptide folding?

Edun, Dean; Flanagan, Meredith R; Serrano, Arnaldo L.

doi:10.1039/d0sc04993j

Cited by 18 publications

(16 citation statements)

References 47 publications

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“…We propose that such structural stability with relatively extended conformation intervenes in the interaction between cationic amino acids and anionic protein/nucleic acids. Our proposal would also be supported by relevant work demonstrating the folding of PR into a helical structure ( Edun et al, 2021 ).…”

Section: Resultsmentioning

confidence: 54%

Phase separation and toxicity of C9orf72 poly(PR) depends on alternate distribution of arginine

Chen

Yamanaka

Ueda

et al. 2021

Journal of Cell Biology

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Arg (R)-rich dipeptide repeat proteins (DPRs; poly(PR): Pro-Arg and poly(GR): Gly-Arg), encoded by a hexanucleotide expansion in the C9ORF72 gene, induce neurodegeneration in amyotrophic lateral sclerosis (ALS). Although R-rich DPRs undergo liquid–liquid phase separation (LLPS), which affects multiple biological processes, mechanisms underlying LLPS of DPRs remain elusive. Here, using in silico, in vitro, and in cellulo methods, we determined that the distribution of charged Arg residues regulates the complex coacervation with anionic peptides and nucleic acids. Proteomic analyses revealed that alternate Arg distribution in poly(PR) facilitates entrapment of proteins with acidic motifs via LLPS. Transcription, translation, and diffusion of nucleolar nucleophosmin (NPM1) were impaired by poly(PR) with an alternate charge distribution but not by poly(PR) variants with a consecutive charge distribution. We propose that the pathogenicity of R-rich DPRs is mediated by disturbance of proteins through entrapment in the phase-separated droplets via sequence-controlled multivalent protein–protein interactions.

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Section: Resultsmentioning

confidence: 54%

Phase separation and toxicity of C9orf72 poly(PR) depends on alternate distribution of arginine

Chen

Yamanaka

Ueda

et al. 2021

Journal of Cell Biology

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“…PEG is a widely used polymeric crowding agent that is known to induce phase separation through the volumetric exclusion effect. 10,[45][46][47] Fig. 1 presents DIC images of the Lys-Alb mixture immediately after adding the PEG stock solution without incubation.…”

Section: Llps Of the Lys-alb Heteroprotein Mixturementioning

confidence: 99%

Micro-Raman spectroscopic analysis of liquid–liquid phase separation

Choi

Chun

Kwak

et al. 2023

Phys. Chem. Chem. Phys.

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“…It is essential to investigate the ultrafast structural and solvation dynamics of biomolecules in living cells since the molecular structure and dynamics of biomolecules like protein can determine their functions and properties. Time‐resolved IR spectroscopy is a powerful experimental tool for observing structural and environmental dynamics of biological systems in aqueous solutions such as conformations, folding, and binding in proteins [1–4] . However, since biomolecules such as peptides and proteins are composed of various amino acids connected through multiple intermolecular and intramolecular interactions, their IR spectra are spectrally complex and entangled.…”

Section: Introductionmentioning

confidence: 99%

Substituent Effects on the Vibrational Properties of the CN Stretch Mode of Aromatic Nitriles: IR Probes Useful for Time‐resolved IR Spectroscopy

Choi

Park

Kwak

et al. 2021

Chemistry An Asian Journal

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Developing ideal IR probes is essential to understand the structure and dynamics of biomolecules with time‐resolved IR spectroscopies and imaging techniques. Especially, nitrile (CN) group has recently been proposed to serve as IR probes of the local environment of proteins. Herein, we investigated the effect of a substituent on the vibrational properties of the benzonitrile. The electron‐donating and withdrawing character of p‐substituent on benzonitrile are expected to modulate the vibrational frequency, molar extinction coefficient, and vibrational lifetime of CN probe. FT‐IR revealed the positive correlation between electron‐donating character and the molar extinction coefficient of CN stretch mode. Infrared pump‐probe (IR‐PP) measurements showed that the vibrational lifetime of CN stretch mode exhibits a relatively weak correlation with the electron‐donating strength. Among the investigated samples, 4‐dimethylamino benzonitrile with the strongest electron‐donating strength shows enhanced absorption and extended vibrational lifetime. Utilizing substituent effects will be a practical strategy to improve the performance of the IR probe.

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Does liquid–liquid phase separation drive peptide folding?

Abstract: Two-dimensional infrared spectroscopy reveals folding of an intrinsically disordered peptide when sequestered into a model “membrane-less” organelle.

Cited by 18 publications

References 47 publications

Phase separation and toxicity of C9orf72 poly(PR) depends on alternate distribution of arginine

Phase separation and toxicity of C9orf72 poly(PR) depends on alternate distribution of arginine

Micro-Raman spectroscopic analysis of liquid–liquid phase separation

Substituent Effects on the Vibrational Properties of the CN Stretch Mode of Aromatic Nitriles: IR Probes Useful for Time‐resolved IR Spectroscopy

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