Exploration of the influence of environmental changes on the conformational and amyloidogenic landscapes of the zinc finger protein DPF3a by combining biophysical and molecular dynamics approaches. - 2025
Exploration of the influence of environmental changes on the conformational and amyloidogenic landscapes of the zinc finger protein DPF3a by combining biophysical and molecular dynamics approaches.
[en] In the past few years, the double PHD fingers 3 (DPF3) protein isoforms (DPF3b and DPF3a) have been identified as new amyloidogenic intrinsically disordered proteins (IDPs). Although such discovery is coherent and promising in light of their involvement in proteinopathies, their amyloidogenic pathway remains largely unexplored. As environmental variations in pH and ionic strength are relevant to DPF3 pathophysiological landscape, we therefore enquired the effect of these physicochemical parameters on the protein structural and prone-to-aggregation properties, by focusing on the more disordered DPF3a isoform. In the present study, we exploited in vitro and in silico strategies by combining spectroscopy, microscopy, and all-atom molecular dynamics methods. Very good consistency and complementary information were found between the experiments and the simulations. Acidification unequivocally abrogated DPF3a fibrillation upon maintaining the protein in highly hydrated and expanded conformers due to extensive repulsion between positively charged regions. In contrast, alkaline pH delayed the aggregation process due to loss in intramolecular contacts and chain decompaction, the extent of which was partly reduced thanks to the compensation of negative charge by arginine side chains. Through screening attractive electrostatic interactions, high ionic strength conditions (300 and 500 mM NaCl) shifted the conformational ensemble towards more swollen, heterogeneous, and less H-bonded structures, which were responsible for slowing down the conversion into β-sheeted species and restricting the fibril elongation. For defining the self-assembly pathway of DPF3a, we unveiled that the protein amyloidogenicity intimately communicates with its conformational landscape, which is particularly sensitive to modification of its physicochemical environment. As such, understanding how to modulate DPF3a conformational ensemble will help designing novel protein-specific strategies for targeting neurodegeneration.
Disciplines :
Chemistry
Author, co-author :
Mignon, Julien; Laboratoire de Chimie Physique des Biomolécules, UCPTS, University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium, Namur Institute of Structured Matter (NISM), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium, Namur Research Institute for Life Sciences (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium. Electronic address: julien.mignon@unamur.be
Leyder, Tanguy; Laboratoire de Chimie Physique des Biomolécules, UCPTS, University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium, Namur Institute of Structured Matter (NISM), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium, Namur Research Institute for Life Sciences (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium. Electronic address: tanguy.leyder@unamur.be
Monari, Antonio; Université Paris Cité and CNRS, ITODYS, 75006 Paris, France. Electronic address: antonio.monari@u-paris.fr
Mottet, Denis ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques
Michaux, Catherine; Laboratoire de Chimie Physique des Biomolécules, UCPTS, University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium, Namur Institute of Structured Matter (NISM), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium, Namur Research Institute for Life Sciences (NARILIS), University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium. Electronic address: catherine.michaux@unamur.be
Language :
English
Title :
Exploration of the influence of environmental changes on the conformational and amyloidogenic landscapes of the zinc finger protein DPF3a by combining biophysical and molecular dynamics approaches.
Publication date :
May 2025
Journal title :
International Journal of Biological Macromolecules
F.R.S.-FNRS - Fonds de la Recherche Scientifique Waalse Gewest ANR - Agence Nationale de la Recherche FRIA - Fund for Research Training in Industry and Agriculture France. Commissariat Général à l'Investissement
Funding text :
The authors are grateful to the Research Unit in Biology of Microorganisms (URBM), as well as to the L.O.S. and Morph-Im platforms of the University of Namur. The authors are also appreciative of the PTCI high-performance computing resource of the University of Namur. This work benefited from computational resources provided by the Consortium des \u00C9quipements de Calcul Intensif (C\u00C9CI), funded by the Belgian National Fund for Scientific Research (F.R.S.-FNRS) under grant n\u00B02.5020.11 and by the Walloon Region, and made available on Lucia, the Tier-1 supercomputer of the Walloon Region, infrastructure funded by the Walloon Region under the grant agreement n\u00B01910247. J. M. and T. L. thank the FNRS for their Research Fellow fellowship and Fund for Research training in Industry and Agriculture (FRIA) Doctoral grant, respectively. A. M. thanks ANR and CGI for their financial support of the present work through Labex SEAM ANR 11 LABEX 086, ANR 11 IDEX 05 02. The support of the IdEx \u201CUniversit\u00E9 Paris 2019\u201D ANR-18-IDEX-0001 is also acknowledged. D. M. and C. M. thank the FNRS for their Senior Research Associate position. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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