Invitée équipe S. Longhi: Stefania Brocca, Université de Milan, Italie -“Solubility, conformation and condensation behavior of disordered proteins: the lesson learnt from synthetic proteins”

Résumé

Intrinsically disordered proteins (IDPs) lack rigid structure, being instead endowed with a high degree of flexibility. In the last two decades, the involvement of IDPs in a plethora of cellular functions has been recognised, including the process of liquid-liquid phase separation (LLPS), which leads to the formation of biomolecular condensates also known as membrane-less organelles. In an extreme form of pleiotropism, it appears possible that a single IDP can perform multiple functions by profoundly altering its solubility, degree of compactness, and ability to form liquid condensates or insoluble, hyperstructured aggregates, as in the case of amyloid fibrils.

This complex and contradictory behaviour of IDPs is largely conferred by their composition, characterised by a high frequency of charged residues, proline and glycine, and a relatively low percentage of hydrophobic and aromatic residues, which typically form the ‘hydrophobic core’ of classically structured proteins.

Recent works highlighting the role of the abundance of charged residues and their ‘patterning’ distribution on conformational and functional aspects of IDPs will be illustrated, often achieved through the rational design of charge permutants.

References

• Tedeschi G. et al. (2017) Aggregation properties of a disordered protein are tunable by pH and depend on its net charge per residue. Biochim Biophys Acta Gen Subj. 1861(11 Pt A):2543-2550. doi: 10.1016/j.bbagen.2017.09.002.
• Tedeschi G. et al. (2018) Conformational response to charge clustering in synthetic intrinsically disordered proteins. Biochim Biophys Acta Gen Subj. 1862(10):2204-2214. doi: 10.1016/j.bbagen.2018.07.011.
• Bianchi G. et al.  (2020) Relevance of Electrostatic Charges in Compactness, Aggregation, and Phase Separation of Intrinsically Disordered Proteins. Int J Mol Sci. 21(17):6208. doi: 10.3390/ijms21176208.
• Bianchi G. et al. (2022) Distribution of Charged Residues Affects the Average Size and Shape of Intrinsically Disordered Proteins. Biomolecules. 12(4):561. doi: 10.3390/biom12040561.
• Bianchi G. et al. Influence of charge distribution in the liquid-liquid phase separation of the N-terminal domain of human topoisomerase 1. Submitted to Int. J. Biol. Mcromol. 2023