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

Abstract

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.

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

“…In particular, many open questions pertaining to the regulation of NT signaling are related to the interplay between proteins and their binding partners, other than the receptors, especially small endogenous molecules (Paoletti & Lamba, 2021 ). Moreover, while the few available reports on this topic are focused on mature NTs, no insights are available on the binding of these small molecules to proNTs.…”

“…Naturally occurring small molecules in vivo have been proposed as physiological endogenous modulators of NGF signaling. Namely, the energy‐carrying molecule ATP has been proposed to play a key role in TrkA receptor signaling mediated by NGF (Hasche et al, 2010 ; Paoletti & Lamba, 2021 ; Paoletti et al, 2021 ). However, the underlying molecular binding mechanism of ATP to proNGF has remained unknown.…”

NGF-NGFR communication inefficiency induces T Cell exhaustion impairing PD-1 immunotherapy in hepatocellular carcinoma

“…The other three neurotrophic factors do not exhibit such positive regulatory roles in cell proliferation. The regulatory role of NGFR in multiple biological processes is known to be dependents on the cooperation of Trks [13,14]. However, the functional role of nerve growth factor receptors and other factors in the in ltrated T cells in hepatocellular carcinoma and the underlying molecular mechanisms have not been elucidated so far.…”

Neurotrophic Activity and Its Modulation by Zinc Ion of a Dimeric Peptide Mimicking the Brain-Derived Neurotrophic Factor N-Terminal Region

“…After its activation, the BDNF–TrkB complex undergoes endocytosis, recycling, or degradation and crucially takes the axonal transport route to sustain neuron survival and differentiation . Furthermore, BDNF/TrkB signaling regulates dendritic branching, the density of spines, and spine morphological specializations, acting both as the mediator and modulator of synaptic plasticity and communication in the CNS. , Intriguingly, several different molecules such as ATP, G-protein-coupled receptor ligands and metal ions can modulate either NTs or their receptors, thus enriching the panorama of signaling cues involved in neurotrophic support. , For the BDNF–TrkB signaling axis, an interesting role is played by zinc, an essential metal ion in brain physiology . Zinc is released from synaptic vesicles of glutamatergic neurons reaching concentrations up to 100 μM in the synaptic cleft, , where it was reported to prompt post-synaptic, BDNF-independent TrkB activation .…”

“…6,7 Intriguingly, several different molecules such as ATP, G-protein-coupled receptor ligands and metal ions can modulate either NTs or their receptors, thus enriching the panorama of signaling cues involved in neurotrophic support. 8,9 For the BDNF−TrkB signaling axis, an interesting role is played by zinc, an essential metal ion in brain physiology. 10 Zinc is released from synaptic vesicles of glutamatergic neurons reaching concentrations up to 100 μM in the synaptic cleft, 11,12 where it was reported to prompt postsynaptic, BDNF-independent TrkB activation.…”