Article (Scientific journals)
Unveiling the Metal-Dependent Aggregation Properties of the C-terminal Region of Amyloidogenic Intrinsically Disordered Protein Isoforms DPF3b and DPF3a.
Leyder, Tanguy; Mignon, Julien; Mottet, Denis et al.
2022In International Journal of Molecular Sciences, 23 (23), p. 15291
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Keywords :
aggregation; amyloid fibrillation; deep-blue autofluorescence; double-PHD fingers 3 (DPF3); electron microscopy; intrinsically disordered protein; metal cations; neurodegenerative diseases; spectroscopy; Intrinsically Disordered Proteins; Amyloid; Metals; Chelating Agents; Protein Isoforms; Cations, Divalent; Humans; Amyloid/metabolism; Chelating Agents/chemistry; Intrinsically Disordered Proteins/chemistry; Inorganic Chemistry; Organic Chemistry; Physical and Theoretical Chemistry; Computer Science Applications; Molecular Biology; General Medicine; Catalysis
Abstract :
[en] Double-PHD fingers 3 (DPF3) is a BAF-associated human epigenetic regulator, which is increasingly recognised as a major contributor to various pathological contexts, such as cardiac defects, cancer, and neurodegenerative diseases. Recently, we unveiled that its two isoforms (DPF3b and DPF3a) are amyloidogenic intrinsically disordered proteins. DPF3 isoforms differ from their C-terminal region (C-TERb and C-TERa), containing zinc fingers and disordered domains. Herein, we investigated the disorder aggregation properties of C-TER isoforms. In agreement with the predictions, spectroscopy highlighted a lack of a highly ordered structure, especially for C-TERa. Over a few days, both C-TERs were shown to spontaneously assemble into similar antiparallel and parallel β-sheet-rich fibrils. Altered metal homeostasis being a neurodegeneration hallmark, we also assessed the influence of divalent metal cations, namely Cu2+, Mg2+, Ni2+, and Zn2+, on the C-TER aggregation pathway. Circular dichroism revealed that metal binding does not impair the formation of β-sheets, though metal-specific tertiary structure modifications were observed. Through intrinsic and extrinsic fluorescence, we found that metal cations differently affect C-TERb and C-TERa. Cu2+ and Ni2+ have a strong inhibitory effect on the aggregation of both isoforms, whereas Mg2+ impedes C-TERb fibrillation and, on the contrary, enhances that of C-TERa. Upon Zn2+ binding, C-TERb aggregation is also hindered, and the amyloid autofluorescence of C-TERa is remarkably red-shifted. Using electron microscopy, we confirmed that the metal-induced spectral changes are related to the morphological diversity of the aggregates. While metal-treated C-TERb formed breakable and fragmented filaments, C-TERa fibrils retained their flexibility and packing properties in the presence of Mg2+ and Zn2+ cations.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Leyder, Tanguy;  Laboratoire de Chimie Physique des Biomolécules, UCPTS, University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium
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, 5000 Namur, Belgium ; Namur Research Institute for Life Sciences (NARILIS), University of Namur, 5000 Namur, Belgium
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, 5000 Namur, Belgium ; Namur Research Institute for Life Sciences (NARILIS), University of Namur, 5000 Namur, Belgium
Language :
English
Title :
Unveiling the Metal-Dependent Aggregation Properties of the C-terminal Region of Amyloidogenic Intrinsically Disordered Protein Isoforms DPF3b and DPF3a.
Publication date :
04 December 2022
Journal title :
International Journal of Molecular Sciences
ISSN :
1661-6596
eISSN :
1422-0067
Publisher :
MDPI AG, Switzerland
Volume :
23
Issue :
23
Pages :
15291
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
F.R.S.-FNRS - Fund for Scientific Research [BE]
Available on ORBi :
since 13 December 2022

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