Nerve Growth Factor Peptides Bind Copper(II) with High Affinity: A Thermodynamic Approach to Unveil Overlooked Neurotrophin Roles.

Antonio Magrì,Enrico Rizzarelli,Diego La Mendola

doi:10.3390/ijms22105085

Abstract

Nerve growth factor (NGF) is a protein essential to neurons survival, which interacts with its receptor as a non-covalent dimer. Peptides belonging to NGF N-terminal domain are able to mimic the activity of the whole protein. Such activity is affected by the presence of copper ions. The metal is released in the synaptic cleft where proteins, not yet identified, may bind and transfer to human copper transporter 1 (hCtr1), for copper uptake in neurons. The measurements of the stability constants of copper complexes formed by amyloid beta and hCtr1 peptide fragments suggest that beta-amyloid (Aβ) can perform this task. In this work, the stability constant values of copper complex species formed with the dimeric form of N-terminal domain, sequence 1–15 of the protein, were determined by means of potentiometric measurements. At physiological pH, NGF peptides bind one equivalent of copper ion with higher affinity of Aβ and lower than hCtr1 peptide fragments. Therefore, in the synaptic cleft, NGF may act as a potential copper chelating molecule, ionophore or chaperone for hCtr1 for metal uptake. Copper dyshomeostasis and mild acidic environment may modify the balance between metal, NGF, and Aβ, with consequences on the metal cellular uptake and therefore be among causes of the Alzheimer’s disease onset.

Highlights

Accepted: 7 May 2021Copper performs several essential functions as a cofactor in many enzymes in the living systems and it is required for the development and function of the human brain [1,2,3]
N-terminal domainenvi1-15 of paper, we report the stability values andofcopper coordination theronment proteinofobtained by disulfide bridge between cysteine units in position (Figure a 30- mer peptide of Nerve growth factor (NGF), namely the dimeric form of N-terminal domain 1- 1)
Potentiometric experiments carried out on N-terminal NGF peptides show that they bind metal with high affinity

Summary

Introduction

Accepted: 7 May 2021Copper performs several essential functions as a cofactor in many enzymes in the living systems and it is required for the development and function of the human brain [1,2,3]. Copper is stored in synaptic vesicles and is released by electrical depolarization in the synaptic cleft of glutamatergic synapses at concentration values that can reach 100 μM [7]. Copper may have inhibitory or stimulating effect on synaptic plasticity, affecting memory and learning processes the mechanisms by which the metal performs these functions remain largely undefined [8,9]. The dual effect may be related to the metal binding by different proteins expressed in neurons and released in the synapses as beta-amyloid (Aβ) [10]. The polypeptide may control copper efflux in the synapses and it has been demonstrated that the polypeptide improves memory formation [11], synaptic plasticity, and neuronal survival [12]

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Discussion

Conclusion