The role of <scp>ATP</scp> in solubilizing <scp>RNA</scp>‐binding protein fused in sarcoma

Aida, Hayato; Shigeta, Yasuteru; Harada, Ryuhei

doi:10.1002/prot.26335

Cited by 17 publications

(10 citation statements)

References 62 publications

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“…Not unexpectedly, both ATP and RNA modulate phase separation biphasically where low concentrations enhance phase separation but high concentrations inhibit droplet formation [ 387 , 396 , 397 , 398 , 399 ]. MD simulations demonstrate succinctly that the dissolution of FUS by ATP-Mg 2+ is promoted by solubilization via the adenine moiety and the phosphate moiety served only to enhance the requisite hydration effect [ 400 ].…”

Section: Light Water and Melatonin: Ancient Synergies In A Modern Worldmentioning

confidence: 99%

Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia

Loh¹,

Reíter

2023

IJMS

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The swift rise in acceptance of molecular principles defining phase separation by a broad array of scientific disciplines is shadowed by increasing discoveries linking phase separation to pathological aggregations associated with numerous neurodegenerative disorders, including Alzheimer’s disease, that contribute to dementia. Phase separation is powered by multivalent macromolecular interactions. Importantly, the release of water molecules from protein hydration shells into bulk creates entropic gains that promote phase separation and the subsequent generation of insoluble cytotoxic aggregates that drive healthy brain cells into diseased states. Higher viscosity in interfacial waters and limited hydration in interiors of biomolecular condensates facilitate phase separation. Light, water, and melatonin constitute an ancient synergy that ensures adequate protein hydration to prevent aberrant phase separation. The 670 nm visible red wavelength found in sunlight and employed in photobiomodulation reduces interfacial and mitochondrial matrix viscosity to enhance ATP production via increasing ATP synthase motor efficiency. Melatonin is a potent antioxidant that lowers viscosity to increase ATP by scavenging excess reactive oxygen species and free radicals. Reduced viscosity by light and melatonin elevates the availability of free water molecules that allow melatonin to adopt favorable conformations that enhance intrinsic features, including binding interactions with adenosine that reinforces the adenosine moiety effect of ATP responsible for preventing water removal that causes hydrophobic collapse and aggregation in phase separation. Precise recalibration of interspecies melatonin dosages that account for differences in metabolic rates and bioavailability will ensure the efficacious reinstatement of the once-powerful ancient synergy between light, water, and melatonin in a modern world.

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Section: Light Water and Melatonin: Ancient Synergies In A Modern Worldmentioning

confidence: 99%

Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia

Loh¹,

Reíter

2023

IJMS

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“…1 Since various debilitating diseases like Alzheimer's and Parkinson's are closely connected to the aggregation of peptides into amyloid fibrils, 2–6 numerous studies have been carried out to examine the effect of ATP on protein aggregation. 7–17…”

Section: Introductionmentioning

confidence: 99%

How ATP suppresses the fibrillation of amyloid peptides: analysis of the free-energy contributions

Do,

Horinek,

Matubayasi

2024

Phys. Chem. Chem. Phys.

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“…Beyond its well-known chemical actions originating from high-energy phosphate bond breaking or allosteric effects during enzymatic catalysis, ATP exhibits contrasting physical biological roles, including the stabilization of soluble proteins (Sridharan et al 2019; Ou et al 2021; Song 2021) and the solubilization of insoluble proteins (Sridharan et al 2019; Patel et al 2017; He, Kang, and Song 2020; Aida, Shigeta, and Harada 2022; Pal and Paul 2020; Sarkar and Mondal 2021). Proteome-wide profiling analyses emphasize ATP-mediated protein stabilization as a prevalent trait within the ensemble of proteins featuring an ATP recognition site (Sridharan et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Elucidating ATP’s Role as Solubilizer of Biomolecular Aggregate

Sarkar,

Gupta,

Mahato

et al. 2024

Preprint

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Proteins occurring in significantly high concentrations in cellular environments (over 100 mg/mL) and functioning in crowded cytoplasm, often face the prodigious challenges of aggregation which are the pathological hallmark of aging and are critically responsible for a wide spectrum of rising human diseases. Adenosine triphosphate (ATP), apart from its conventional activity as energy carrier, has been recently reported to play crucial roles in cellular protein homeostasis involving stabilization of soluble proteins and solubilization of insoluble candidates for driving different biological processes. However, the potential role of ATP in modulating structural plasticity of the insoluble proteins and its probable link with ATP's solubilizing effect have escaped the mainstream investigation. Here we first computationally simulate how ATP influences the conformational landscape of globular mini-protein Trp-cage and intrinsically disordered protein Aβ40, which are situated at mutually opposite ends of the structural spectrum.Subsequently a joint-venture of complementary wet-lab experiments and computer simulation pin-points that ATP enhances protein solubility by unwinding protein chains via direct ATP-protein preferential interaction in a protein-specific manner and prevents condensation of aggregation-prone Aβ40 as well as promotes dissolution of pre-formed aggregates. Our study also establishes the superiority of ATP as a solubilizer of protein aggregate over traditional chemical hydrotrope (NaXS) and highlights promising potential implications and ATP-based therapeutic interventions in protein-aggregation related diseases.

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The role of ATP in solubilizing RNA‐binding protein fused in sarcoma

Cited by 17 publications

References 62 publications

Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia

Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia

How ATP suppresses the fibrillation of amyloid peptides: analysis of the free-energy contributions

Elucidating ATP’s Role as Solubilizer of Biomolecular Aggregate

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