Unveiling the Metal-Dependent Aggregation Properties of the C-terminal Region of Amyloidogenic Intrinsically Disordered Protein Isoforms DPF3b and DPF3a

Titre traduit de la contribution: Caractérisation des propriétés d'agrégation métal-dépendantes de la région C-terminale des isoformes amyloïdogènes intrinsèquement désordonnées DPF3b et DPF3a

Tanguy Leyder, Julien Mignon, Denis Mottet, Catherine Michaux

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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.
Titre traduit de la contributionCaractérisation des propriétés d'agrégation métal-dépendantes de la région C-terminale des isoformes amyloïdogènes intrinsèquement désordonnées DPF3b et DPF3a
langue originaleAnglais
Numéro d'article15291
Nombre de pages29
journalInternational Journal of Molecular Sciences
Numéro de publication23
Les DOIs
Etat de la publicationPublié - 4 déc. 2022


  • Double doigt PHD 3 (DPF3)
  • Protéine intrinsèquement désordonnée
  • Maladies neurodégénératives
  • Agrégation
  • Fibrillation amyloïde
  • Cations métalliques
  • Spectroscopie
  • Autofluorescence du bleu profond
  • Microscopie électronique

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