PhD thesis defense in chemical sciences by Julien MIGNON

Unravelling the disorder-aggregation-properties relationships of the amyloidogenic intrinsically disordered proteins DPF3: towards new anti-amyloid strategies

Candidate

Julien MIGNON

Promoter

Prof. Catherine MICHAUX, UNamur, Department of chemistry, Unit of theoretical and structural physico-chemistry (UCPTS), Laboratory of Physical Chemistry of Biomolecules (CPB)

Jury

• Prof. Benoît CHAMPAGNE (UNamur), Président
• Prof. Catherine MICHAUX (UNamur), Secrétaire
• Prof. Sonia LONGHI (Aix-Marseille Université)
• Prof. Antonio MONARI (Université Paris-Cité)
• Prof. Denis MOTTET (Université de Liège)
• Prof. Vincent RAUSSENS (Université Libre de Bruxelles)
• Prof. Peter TOMPA (Vrije Universiteit Brussel)

Summary

Amongst the top leading causes of death and disability, cancer and neurodegenerative diseases are overrepresented worldwide. These pathologies arise from the dysregulation of the structure and function of protein molecules. Whilst the protein realm becomes more and more vast, one peculiar group of polypeptides stands out. Intrinsically disordered proteins (IDPs), defined as structure-less and dynamic ensembles of rapidly interconverting conformers, are increasingly recognised as prime therapeutical targets. However, due to their inherent plasticity, heterogeneity, and promiscuity, they elude traditional structure-based characterisation methods and drug design approaches. As such, they require the combination of diverse biophysical and computational techniques to decipher their disorder-function-aggregation properties in diseases.

In such context, this thesis considers the human double PHD fingers 3 (DPF3) protein and its isoforms (DPF3b and DPF3a), reported as epigenetic regulators notably involved in numerous oncogenic pathways and neurological disorders. While their pathophysiological repertoire appears well-documented, very little is currently known about their respective structure-function relationships. Nevertheless, a few clues scattered across the literature hinted that they may belong to the class of IDPs, which prompted the present research project to elucidate the disorder-associated features of DPF3 proteins.

Upon exploiting spectroscopy, light scattering, microscopy, sequence-based prediction, and molecular dynamics methods, DPF3 isoforms were revealed to be IDPs that are highly sensitive to changes in their physicochemical environment. Furthermore, it was discovered that both isoforms are prone to shape their conformational landscape towards the formation of high-order oligomers elongating into amyloid fibrils. Such supramolecular assemblies are organised around a cross β-sheeted core and are known to accumulate in neurodegeneration processes. Intriguingly, DPF3 fibrils exhibited unique photoluminescence phenomena that were revealed to be versatile and intimately associated to the fibrillar architecture. Taken as a whole, this thesis shed light on the previously unnoticed disorder-aggregation properties relationships of DPF3 isoforms that are not only consistent with their pathological range but will also help paving the way for the development of novel protein-specific anticancer and anti-amyloid strategies.