Paoletti, F, Covaceuszach, S, Cassetta, A et al. (6 more authors) (2023) Distinct conformational changes occur within the intrinsically unstructured pro-domain of pro-Nerve Growth Factor in the presence of ATP and Mg2+. Protein Science, 32 (2). e4563. ISSN 0961-8368
Abstract
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2023 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society. This is an open access article published under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. |
Keywords: | conformational rearrangement of the Intrinsically Unstructured Domain (IUD), Hydrogen Deuterium eXchange-Mass Spectrometry (HDX-MS), intermolecular interactions, NMR spectroscopy, proNGF, Small Angle X-ray Scattering (SAXS) |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Molecular and Cellular Biology (Leeds) > Biomolecular Mass Spectroscopy (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 18 Jan 2023 11:58 |
Last Modified: | 25 Jun 2023 23:13 |
Status: | Published |
Publisher: | Wiley |
Identification Number: | 10.1002/pro.4563 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:195336 |