In search for novel functions of adenosine 5′-triphosphate (ATP) in the heart

Meyer, Thomas; Voigt, Niels

doi:10.1093/cvr/cvx207

Cited by 7 publications

(4 citation statements)

References 17 publications

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“…Protein aggregation/fibrillation has been now established to be the universal hallmark of an increasing spectrum of human diseases beyond neurodegenerative diseases, which also include cardiac dysfunction, eye cataract, degeneration of muscle and bone, as well as aging down to E. coli 24,[39][40][41][42][43][44][45][46][47][48][49][50] . Out of various factors that modulate aggregation/fibrillation of the folded proteins, two key determinants are thermodynamic stability and conformational dynamics.…”

Section: Discussionmentioning

confidence: 99%

Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

Dang

Song

2021

Sci Rep

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TDP-43 and hnRNPA1 contain tandemly-tethered RNA-recognition-motif (RRM) domains, which not only functionally bind an array of nucleic acids, but also participate in aggregation/fibrillation, a pathological hallmark of various human diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), alzheimer's disease (AD) and Multisystem proteinopathy (MSP). Here, by DSF, NMR and MD simulations we systematically characterized stability, ATP-binding and conformational dynamics of TDP-43 and hnRNPA1 RRM domains in both tethered and isolated forms. The results reveal three key findings: (1) upon tethering TDP-43 RRM domains become dramatically coupled and destabilized with Tm reduced to only 49 °C. (2) ATP specifically binds TDP-43 and hnRNPA1 RRM domains, in which ATP occupies the similar pockets within the conserved nucleic-acid-binding surfaces, with the affinity slightly higher to the tethered than isolated forms. (3) MD simulations indicate that the tethered RRM domains of TDP-43 and hnRNPA1 have higher conformational dynamics than the isolated forms. Two RRM domains become coupled as shown by NMR characterization and analysis of inter-domain correlation motions. The study explains the long-standing puzzle that the tethered TDP-43 RRM1–RRM2 is particularly prone to aggregation/fibrillation, and underscores the general role of ATP in inhibiting aggregation/fibrillation of RRM-containing proteins. The results also rationalize the observation that the risk of aggregation-causing diseases increases with aging.

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Section: Discussionmentioning

confidence: 99%

Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

Dang

Song

2021

Sci Rep

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“…Some hydrotropes seem to assume micellular structures while others facilitate solubilization through the formation of more open, planar structures ( Schreier et al, 2000 ). Meyer and Voigt, ( Meyer and Voigt, 2017 ) in discussing the possible role of ATP as a hydrotrope, point out that ATP would not be expected to form micelles but does have the chemical features needed to serve as a hydrotrope. ATP is able to function as a hydrotrope because it is an amphiphile, a compound with hydrophilic and hydrophobic properties.…”

Section: Introductionmentioning

confidence: 99%

Dual roles for ATP in the regulation of phase separated protein aggregates in Xenopus oocyte nucleoli

Hayes

Peuchen

Dovic̀hi

et al. 2018

eLife

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For many proteins, aggregation is one part of a structural equilibrium that can occur. Balancing productive aggregation versus pathogenic aggregation that leads to toxicity is critical and known to involve adenosine triphosphate (ATP) dependent action of chaperones and disaggregases. Recently a second activity of ATP was identified, that of a hydrotrope which, independent of hydrolysis, was sufficient to solubilize aggregated proteins in vitro. This novel function of ATP was postulated to help regulate proteostasis in vivo. We tested this hypothesis on aggregates found in Xenopus oocyte nucleoli. Our results indicate that ATP has dual roles in the maintenance of protein solubility. We provide evidence of endogenous hydrotropic action of ATP but show that hydrotropic solubilization of nucleolar aggregates is preceded by a destabilizing event. Destabilization is accomplished through an energy dependent process, reliant upon ATP and one or more soluble nuclear factors, or by disruption of a co-aggregate like RNA.

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“…Protein aggregation/fibrillation has been now established to be the universal hallmark of an increasing spectrum of human diseases beyond neurodegenerative diseases, which also include cardiac dysfunction, eye cataract, degeneration of muscle and bone, as well as aging down to E. coli (24,(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48). Out of various factors that modulate aggregation/fibrillation of the folded proteins, two key determinants are thermodynamic stability and conformational dynamics.…”

Section: Discussionmentioning

confidence: 99%

Stabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

Dang

Song

2020

Preprint

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TDP-43 and hnRNPA1 contain tandemly-tethered RRM domains, which not only functionally bind an array of nucleic acids, but also participate in aggregation/fibrillation, a pathological hallmark of various human diseases including ALS, FTD, AD and MSP. Here, by DSF, NMR and MD simulations we systematically characterized stability, ATP-binding and conformational dynamics of TDP-43 and hnRNPA1 RRM domains in both tethered and isolated forms. The results reveal three key findings: 1) very unexpectedly, upon tethering TDP-43 RRM domains become dramatically coupled and destabilized with Tm reduced to only 49 °C. 2) ATP specifically binds TDP-43 and hnRNPA1 RRM domains, in which ATP occupies the similar pockets within the conserved nucleic-acid-binding surfaces, with the affinity higher to the tethered than isolated forms. 3) MD simulations indicate that the tethered RRM domains of TDP-43 and hnRNPA1 have higher conformational dynamics than the isolated forms. Two RRM domains become coupled as shown by NMR characterization and analysis of inter-domain correlation motions. The study explains the long-standing puzzle that the tethered TDP-43 RRM1-RRM2 is particularly prone to aggregation/fibrillation, and underscores the general role of ATP in inhibiting aggregation/fibrillation of RRM-containing proteins. The results also rationalize the observation that the risk of aggregation-causing diseases increases with aging.

show abstract

In search for novel functions of adenosine 5′-triphosphate (ATP) in the heart

Cited by 7 publications

References 17 publications

Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

Tethering-induced destabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

Dual roles for ATP in the regulation of phase separated protein aggregates in Xenopus oocyte nucleoli

Stabilization and ATP-binding for tandem RRM domains of ALS-causing TDP-43 and hnRNPA1

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