Structural characterisation of amyloidogenic intrinsically disordered zinc finger protein isoforms DPF3b and DPF3a

Mignon, Julien; Mottet, Denis; Leyder, Tanguy; Uversky, Vladimir N.; Perpète, Éric A.; Michaux, Catherine

doi:10.1016/j.ijbiomac.2022.07.102

Cited by 12 publications

(12 citation statements)

References 81 publications

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“…These dual emission modes have been associated with amyloidogenic proteins and, most notably, have been reported for transthyretin and DPF3 isoforms [ 16 , 17 , 66 , 67 ]. Although the mechanism underlying this phenomenon, referred to as deep-blue autofluorescence (dbAF), remains debated, many studies propose that it arises from low-energy transitions caused by electron delocalisation through hydrogen bonds within the highly stable β-sheet network in amyloid aggregates [ 68 , 69 , 70 ].…”

Section: Resultsmentioning

confidence: 98%

“…Recently, we demonstrated that both full-length (FL) DPF3 isoforms are able to aggregate in vitro with different kinetics into morphologically similar amyloid fibrils [ 17 ]. Herein, the aggregation propensity of C-TERb and C-TERa was also spectroscopically investigated over an incubation period of four days (96 h) at ~20 °C.…”

Section: Resultsmentioning

confidence: 99%

“…Due to the large diversity in sequence composition, the formation of dbAF-emitting fluorophores is most likely protein-specific, resulting in a vast array of unique λ em in the visible range. Still, dbAF is a sensitive and reliable intrinsic fluorescence method for probing structural changes, especially for aggregation-prone proteins [ 17 , 67 ].…”

Section: Resultsmentioning

confidence: 99%

“…As unravelled in our latest studies, DPF3 is an intrinsically disordered protein (IDP) [ 16 , 17 ]. The two isoforms have a high disorder content, lack a hydrophobic core, and display an expanded and/or collapsed conformational ensemble.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast with DPF3b, DPF3a rapidly aggregates, likely due to its highly dynamic C-terminal domain. Given all these properties, DPF3 isoforms are considered as new amyloidogenic IDPs [ 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

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

Leyder

Mignon

Mottet

et al. 2022

IJMS

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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.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Leyder

Mignon

Mottet

et al. 2022

IJMS

Self Cite

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Protein aggregation and neurodegenerative disease: Structural outlook for the novel therapeutics

2023

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Before the controversial approval of humanized monoclonal antibody lecanemab, which binds to the soluble amyloid‐β protofibrils, all the treatments available earlier, for Alzheimer's disease (AD) were symptomatic. The researchers are still struggling to find a breakthrough in AD therapeutic medicine, which is partially attributable to lack in understanding of the structural information associated with the intrinsically disordered proteins and amyloids. One of the major challenges in this area of research is to understand the structural diversity of intrinsically disordered proteins under in vitro conditions. Therefore, in this review, we have summarized the in vitro applications of biophysical methods, which are aimed to shed some light on the heterogeneity, pathogenicity, structures and mechanisms of the intrinsically disordered protein aggregates associated with proteinopathies including AD. This review will also rationalize some of the strategies in modulating disease‐relevant pathogenic protein entities by small molecules using structural biology approaches and biophysical characterization. We have also highlighted tools and techniques to simulate the in vivo conditions for native and cytotoxic tau/amyloids assemblies, urge new chemical approaches to replicate tau/amyloids assemblies similar to those in vivo conditions, in addition to designing novel potential drugs.

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Computational Prediction of Linear Interacting Peptides

Malhis,

Gsponer

2024

Methods in Molecular Biology

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Structural characterisation of amyloidogenic intrinsically disordered zinc finger protein isoforms DPF3b and DPF3a

Cited by 12 publications

References 81 publications

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

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

Protein aggregation and neurodegenerative disease: Structural outlook for the novel therapeutics

Computational Prediction of Linear Interacting Peptides

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