Endogenous modulators of neurotrophin signaling: Landscape of the transient ATP-NGF interactions

Paoletti, Francesca; Merzel, Franci; Cassetta, Alberto; Ogris, Iza; Covaceuszach, Sonia; Grdadolnik, Jože; Lamba, Doriano; Grdadolnik, Simona Golič

doi:10.1016/j.csbj.2021.05.009

Cited by 6 publications

(16 citation statements)

References 75 publications

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“…Recently, a study has been reported describing a thorough structural/biophysical study to characterize the interaction of ATP with recombinant human NGF (rhNGF). This study describes the molecular determinants of the interactions between ATP and rhNGF and allows to unveil the previously unknown binding sites on the molecular surface and the ligand’s orientation [ 5 ]. According to Isothermal Titration Calorimetry (ITC) data, ATP binds rhNGF with a low affinity (mM range), as confirmed by Surface Plasmon Resonance (SPR) and Saturation Transfer Difference NMR (STD-NMR).…”

Section: Ngf and Molecules Carrying Phosphate Groupsmentioning

confidence: 99%

“…The functional role of the ATP-rhNGF interaction in the context of TrkA and p75 NTR receptors was studied by SPR. Also, the investigation of the functional role of divalent ions (Mg 2+ or Zn 2+ ) in conjunction with ATP allowed to conclude that the relative stoichiometry of ATP-ion-rhNGF is a key factor for the regulation of the binding effect [ 5 ]. The structural/computation study pinpoints ATP as a genuine endogenous modulator of NGF signaling in vivo, in health and disease conditions.…”

Section: Ngf and Molecules Carrying Phosphate Groupsmentioning

confidence: 99%

“…It is interesting to mention that the NGF has also been found in llama seminal plasma as the ovulation-inducing factor (OIF). Once the X-ray crystal structure of the protein was solved (PDB ID: 4EFV [ 8 ]), it revealed the presence of a phosphate group in close vicinity to the ATP binding site reported by Paoletti et al [ 5 ]. This further corroborates the importance of phosphate ion carrying ligands to NGF.…”

Section: Ngf and Molecules Carrying Phosphate Groupsmentioning

confidence: 99%

“…SPR, ITC and 1D 1 H STD-NMR pinpoint to low affinity (mM range) ATP-rhNGF binding. ITC titration data returned a K D of 1.38 mM, underlining transient interactions with weak affinities [ 5 ].…”

Section: Ngf and Molecules Carrying Phosphate Groupsmentioning

confidence: 99%

“…Recently, it became clear that the molecular bioactivity of NGF is associated to other actors, whose role in NGF signaling has been often overlooked. These are small endogenous biomolecules (nucleotides, lipids and carbohydrates) involved in many intracellular pathways [ 5 , 6 , 7 , 8 , 9 ]. It thus remains crucial to elucidate the molecular and chemical topology of the partners involved in neurotrophins signaling.…”

Section: Introductionmentioning

confidence: 99%

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Small Endogenous Ligands Modulation of Nerve Growth Factor Bioactivity: A Structural Biology Overview

Paoletti

Lamba

2021

Cells

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Experiments with cell cultures and animal models have provided solid support for the assumption that Nerve Growth Factor (NGF) plays a key role in the regulation of neuronal cell survival and death. Recently, endogenous ligands have been proposed as physiological modulators of NGF biological activity as part of this regulatory cascade. However, the structural and mechanistic determinants for NGF bioactivity remain to be elucidated. We recently unveiled, by an integrated structural biology approach, the ATP binding sites of NGF and investigated the effects on TrkA and p75NTR receptors binding. These results pinpoint ATP as a genuine endogenous modulator of NGF signaling, paving the way to the characterization of not-yet-identified chemical diverse endogenous biological active small molecules as novel modulators of NGF. The present review aims at providing an overview of the currently available 3D structures of NGF in complex with different small endogenous ligands, featuring the molecular footprints of the small molecules binding. This knowledge is essential for further understanding the functional role of small endogenous ligands in the modulation of neurotrophins signaling in physiological and pathological conditions and for better exploiting the therapeutic potentialities of NGF.

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Section: Ngf and Molecules Carrying Phosphate Groupsmentioning

confidence: 99%

Section: Ngf and Molecules Carrying Phosphate Groupsmentioning

confidence: 99%

Section: Ngf and Molecules Carrying Phosphate Groupsmentioning

confidence: 99%

Section: Ngf and Molecules Carrying Phosphate Groupsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Small Endogenous Ligands Modulation of Nerve Growth Factor Bioactivity: A Structural Biology Overview

Paoletti

Lamba

2021

Cells

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Distinct conformational changes occur within the intrinsically unstructured pro‐domain of pro‐Nerve Growth Factor in the presence of ATP and Mg²⁺

et al. 2023

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Nerve growth factor (NGF), the prototypical neurotrophic factor, is involved in the maintenance and growth of specific neuronal populations, whereas its precursor, proNGF, is involved in neuronal apoptosis. Binding of NGF or proNGF to TrkA, p75NTR, and VP10p receptors triggers complex intracellular signaling pathways that can be modulated by endogenous small‐molecule ligands. Here, we show by isothermal titration calorimetry and NMR that ATP binds to the intrinsically disordered pro‐peptide of proNGF with a micromolar dissociation constant. We demonstrate that Mg2+, known to play a physiological role in neurons, modulates the ATP/proNGF interaction. An integrative structural biophysics analysis by small angle X‐ray scattering and hydrogen‐deuterium exchange mass spectrometry unveils that ATP binding induces a conformational rearrangement of the flexible pro‐peptide domain of proNGF. This suggests that ATP may act as an allosteric modulator of the overall proNGF conformation, whose likely distinct biological activity may ultimately affect its physiological homeostasis.

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ATP binding to Nerve Growth Factor (NGF) and pro-Nerve Growth Factor (proNGF): an endogenous molecular switch modulating neurotrophins activity

Paoletti

2024

Biochemical Society Transactions

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ATP has recently been reconsidered as a molecule with functional properties which go beyond its recognized role of the energetic driver of the cell. ATP has been described as an allosteric modulator as well as a biological hydrotrope with anti-aggregation properties in the crowded cellular environment. The role of ATP as a modulator of the homeostasis of the neurotrophins (NTs), a growth factor protein family whose most known member is the nerve growth factor (NGF), has been investigated. The modulation of NTs by small endogenous ligands is still a scarcely described area, with few papers reporting on the topic, and very few reports on the molecular determinants of these interactions. However, a detailed atomistic description of the NTs interaction landscape is of urgent need, aiming at the identification of novel molecules as potential therapeutics and considering the wide range of potential pharmacological applications for NGF and its family members. This mini-review will focus on the unique cartography casting the interactions of the endogenous ligand ATP, in the interaction with NGF as well as with its precursor proNGF. These interactions revealed interesting features of the ATP binding and distinct differences in the binding mode between the highly structured mature NGF and its precursor, proNGF, which is characterized by an intrinsically unstructured domain. The overview on the recent available data will be presented, together with the future perspectives on the field.

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Endogenous modulators of neurotrophin signaling: Landscape of the transient ATP-NGF interactions

Abstract: Graphical abstract

Cited by 6 publications

References 75 publications

Small Endogenous Ligands Modulation of Nerve Growth Factor Bioactivity: A Structural Biology Overview

Small Endogenous Ligands Modulation of Nerve Growth Factor Bioactivity: A Structural Biology Overview

Distinct conformational changes occur within the intrinsically unstructured pro‐domain of pro‐Nerve Growth Factor in the presence of ATP and Mg²⁺

ATP binding to Nerve Growth Factor (NGF) and pro-Nerve Growth Factor (proNGF): an endogenous molecular switch modulating neurotrophins activity

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Endogenous modulators of neurotrophin signaling: Landscape of the transient ATP-NGF interactions

Abstract: Graphical abstract

Cited by 6 publications

References 75 publications

Small Endogenous Ligands Modulation of Nerve Growth Factor Bioactivity: A Structural Biology Overview

Small Endogenous Ligands Modulation of Nerve Growth Factor Bioactivity: A Structural Biology Overview

Distinct conformational changes occur within the intrinsically unstructured pro‐domain of pro‐Nerve Growth Factor in the presence of ATP and Mg2+

ATP binding to Nerve Growth Factor (NGF) and pro-Nerve Growth Factor (proNGF): an endogenous molecular switch modulating neurotrophins activity

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Distinct conformational changes occur within the intrinsically unstructured pro‐domain of pro‐Nerve Growth Factor in the presence of ATP and Mg²⁺