Paoletti, Francesca; Covaceuszach, Sonia; Cassetta, Alberto; Calabrese, Antonio N; Novak, Urban; Konarev, Petr; Grdadolnik, Jože; Lamba, Doriano; Golič Grdadolnik, Simona (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. Wiley-Blackwell 10.1002/pro.4563
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Protein_Science_-_2023_-_Paoletti_-_Distinct_conformational_changes_occur_within_the_intrinsically_unstructured_pro_domain.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (2MB) | Preview |
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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Medical Oncology |
UniBE Contributor: |
Novak, Urban |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
0961-8368 |
Publisher: |
Wiley-Blackwell |
Language: |
English |
Submitter: |
Rebeka Gerber |
Date Deposited: |
16 Mar 2023 06:58 |
Last Modified: |
16 Mar 2023 23:27 |
Publisher DOI: |
10.1002/pro.4563 |
PubMed ID: |
36605018 |
Uncontrolled Keywords: |
Hydrogen-Deuterium eXchange-Mass Spectrometry (HDX-MS) NMR spectroscopy Small Angle X-ray Scattering (SAXS) conformational rearrangement of the Intrinsically Unstructured Domain (IUD) intermolecular interactions proNGF |
BORIS DOI: |
10.48350/180108 |
URI: |
https://boris.unibe.ch/id/eprint/180108 |
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