Aβ, IAPP, α-synuclein, and prion proteins belong to the amyloidogenic intrinsically disordered proteins' family; indeed, they lack well defined secondary and tertiary structures. It is generally acknowledged that they are involved, respectively, in Alzheimer's, Type II Diabetes Mellitus, Parkinson's, and Creutzfeldt-Jakob's diseases. The molecular mechanism of toxicity is under intense debate, as many hypotheses concerning the involvement of the amyloid and the toxic oligomers have been proposed. However, the main role is represented by the interplay of protein and the cell membrane. Thus, the understanding of the interaction mechanism at the molecular level is crucial to shed light on the dynamics driving this phenomenon. There are plenty of factors influencing the interaction as mentioned above, however, the overall view is made trickier by the apparent irreproducibility and inconsistency of the data reported in the literature. Here, we contextualized this topic in a historical, and even more importantly, in a future perspective. We introduce two novel insights: the chemical equilibrium, always established in the aqueous phase between the free and the membrane phospholipids, as mediators of protein-transport into the core of the bilayer, and the symmetry-breaking of oligomeric aggregates forming an alternating array of partially ordered and disordered monomers.

Department of Biophysical Chemistry J Heyrovský Institute of Physical Chemistry Academy of Sciences of the Czech Republic Dolejškova 3 18223 Prague 8 Czech Republic

Dipartimento di Scienze Chimiche Università degli Studi di Catania Viale Andrea Doria 6 95125 Catania Italy

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Pappalardo M., Sciacca M., Milardi D., Grasso D., La Rosa C. Thermodynamics of azurin folding: The role of copper ion. J. Therm. Anal. Calorim. 2008;93:575–581. doi: 10.1007/s10973-007-8422-z. DOI

La Rosa C., Milardi D., Amato E., Pappalardo M., Grasso D. Molecular mechanism of the inhibition of cytochrome c aggregation by Phe-Gly. Arch. Biochem. Biophys. 2005;435:182–189. doi: 10.1016/j.abb.2004.12.006. PubMed DOI

Sciacca M., Milardi D., Pappalardo M., La Rosa C., Grasso D. Role of electrostatics in the thermal stability of ubiquitin: A combined DSC and MM study. J. Therm. Anal. Calorim. 2006;86:311–314. doi: 10.1007/s10973-005-7467-0. DOI

Manetto G., La Rosa C., Grasso D., Milardi D. Evaluation of thermodynamic properties of irreversible protein thermal unfolding measured by DSC. J. Therm. Anal. Calorim. 2005;80:263–270. doi: 10.1007/s10973-005-0646-1. DOI

Romanucci V., Milardi D., Campagna T., Gaglione M., Messere A., D’Urso A., Crisafi E., La Rosa C., Zarrelli A., Balzarini J., et al. Synthesis, biophysical characterization and anti-HIV activity of d (TG 3 AG) quadruplexes bearing hydrophobic tails at the 5′-end. Bioorg. Med. Chem. 2014;22:960–966. doi: 10.1016/j.bmc.2013.12.051. PubMed DOI

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Milardi D., Pappalardo M., Grasso D.M., La Rosa C. Unveiling the unfolding pathway of FALS associated G37R SOD1 mutant: A computational study. Mol. BioSyst. 2010;6:1032–1039. doi: 10.1039/b918662j. PubMed DOI

Lella M., Mahalakshmi R. Metamorphic Proteins: Emergence of Dual Protein Folds from One Primary Sequence. Biochemistry. 2017;56:2971–2984. doi: 10.1021/acs.biochem.7b00375. PubMed DOI

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Lipid-Chaperone Hypothesis: A Common Molecular Mechanism of Membrane Disruption by Intrinsically Disordered Proteins