Aurélien Lorin

In Silico tilted properties of the 67-78 fragment of alpha-synuclein are responsible for membrane destabilization and neurotoxicity

α‐Synuclein is a 140 residue protein associated with Parkinsons disease. Intraneural inclusions called Lewy bodies and Lewy neurites are mainly composed of α‐synuclein aggregated into amyloid fibrils. Other amyloidogenic proteins, such as the β amyloid peptide involved in Alzheimers disease and the prion protein (PrP) associated with Creuztfeldt‐Jakobs disease, are known to possess “tilted peptides”. These peptides are short protein fragments that adopt an oblique orientation at a hydrophobic/hydrophilic interface, which enables destabilization of the membranes. In this paper, sequence analysis and molecular modelling predict that the 67–78 fragment of α‐synuclein is a tilted peptide. Its destabilizing properties were tested experimentally. The α‐synuclein 67–78 peptide is able to induce lipid mixing and leakage of unilamellar liposomes. The neuronal toxicity, studied using human neuroblastoma cells, demonstrated that the α‐synuclein 67–78 peptide induces neurotoxicity. A mutant designed by molecular modelling to be amphipathic was shown to be significantly less fusogenic and toxic than the wild type. In conclusion, we have identified a tilted peptide in α‐synuclein, which could be involved in the toxicity induced during amyloidogenesis of α‐synuclein. Proteins 2007.

The “Tilted Peptide Theory” Links Membrane Insertion Properties and Fusogenicity of Viral Fusion Peptides

Class I fusion glycoproteins of viruses are involved in the fusion between viral envelope and cell membrane. A region located in the N-terminal domain of these glycoproteins, called the fusion peptide, is essential for fusion. Fusion peptides are able to induce by themselves in vitro membrane fusion. In this paper, we review the properties of those peptides related to their fusogenicity, in particular the correlation existing between their ability to insert obliquely in membranes and fusogenicity. This relation notably allows predicting successfully the minimal region of some fusion peptides sufficient to induce significant in vitro fusion. The notion of obliquity and fusogenicity is discussed in terms of the existing proposed mechanisms for viral fusion.

Mode of Membrane Interaction and Fusogenic Properties of a de Novo Transmembrane Model Peptide Depend on the Length of the Hydrophobic Core

Model peptides composed of alanine and leucine residues are often used to mimic single helical transmembrane domains. Many studies have been carried out to determine how they interact with membranes. However, few studies have investigated their lipid-destabilizing effect. We designed three peptides designated KALRs containing a hydrophobic stretch of 14, 18, or 22 alanines/leucines surrounded by charged amino acids. Molecular modeling simulations in an implicit membrane model as well as attenuated total reflection-Fourier transform infrared analyses show that KALR is a good model of a transmembrane helix. However, tryptophan fluorescence and attenuated total reflection-Fourier transform infrared spectroscopy indicate that the extent of binding and insertion into lipids increases with the length of the peptide hydrophobic core. Although binding can be directly correlated to peptide hydrophobicity, we show that insertion of peptides into a membrane is determined by the length of the peptide hydrophobic core. Functional studies were performed by measuring the ability of peptides to induce lipid mixing and leakage of liposomes. The data reveal that whereas KALR14 does not destabilize liposomal membranes, KALR18 and KALR22 induce 40 and 50% of lipid-mixing, and 65 and 80% of leakage, respectively. These results indicate that a transmembrane model peptide can induce liposome fusion in vitro if it is long enough. The reasons for the link between length and fusogenicity are discussed in relation to studies of transmembrane domains of viral fusion proteins. We propose that fusogenicity depends not only on peptide insertion but also on the ability of peptides to destabilize the two leaflets of the liposome membrane.