Destabilization Of A Model Membrane By A Predicted Fusion Peptide Of Fertilin Alpha

peer reviewedThe subunit a of the guinea pig fertilin (previously known as PH-30, an integral membrane protein involved in sperm-egg binding and fusion) is predicted to be a potential fusion protein.The structure of this putative fusion protein was analysed by molecular modeling and we have found a peptidic sequence of 17 residues (D83-P99) organized in helix that inserts obliquely in lipid phases. The effect of ths synthesized peptide was studied on a model membrane by 3lP NMR and light scattering. It appears to increase the size of lipid vesicles and induces structural odifications. We interpret these observations as a destabilization of the lipid organization by this peptide because of its tilted insertion in phospholipid layers. This destabilization could favor membrane fusion

Piracetam-induced changes to membrane physical properties. A combined approach by 31P nuclear magnetic resonance and conformational analysis.

Piracetam, Nootropil (2-oxo-1-pyrrolidine acetamide), is a drug promoting erythrocyte deformability. To establish the mode of action of this compound, we have investigated its influence on the organization of model phospholipid membranes. 31P NMR data show that the drug induces a structural modification in liposomes made of phosphatidylcholine and phosphatidylethanolamine. Our conformational analysis results have allowed the interpretation of the effect of piracetam on these model membranes: the specific interaction between the drug molecules and the phosphate headgroups induces a new organization of the lipids favouring formation of mobile drug-phospholipid complexes that exhibit an isotropic-type signal in the 31P NMR spectra.Journal ArticleResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

Influence of the mode of insertion of SIV peptides into membranes on the structure of model membrane as studied by 31P NMR.

The influence on model membrane organization of a fusion peptide of SIV and of a nonfusogenic mutant of this peptide was examined by molecular modeling and by 31P NMR. The calculated mode of insertion of the fusion peptide shows that it adopts an oblique orientation towards the lipid-water interface and that this fusion peptide induces a destabilization of the bilayer structure of multilamellar vesicles as evidenced by 31P NMR observations. The SIV mutant showing a more vertical insertion into lipid layers is unable to induce nonlamellar structures. This study reinforces the correlation between fusogenic activity, induction of structures not organized in extended bilayers, and calculated mode of insertion of peptides into lipid layers

Piracetam-induced Changes To Membrane Physical-properties - a Combined Approach By P-31 Nuclear-magnetic-resonance and Conformational-analysis

Piracetam, Nootropil(R) (2-oxo-1-pyrrolidine acetamide), is a drug promoting erythrocyte deformability. To establish the mode of action of this compound, we have investigated its influence on the organization of model phospholipid membranes. P-31 NMR data show that the drug induces a structural modification in liposomes made of phosphatidylcholine and phosphatidylethanolamine. Our conformational analysis results have allowed the interpretation of the effect of piracetam on these model membranes: the specific interaction between the drug molecules and the phosphate headgroups induces a new organization of the lipids favouring formation of mobile drug-phospholipid complexes that exhibit an isotropic-type signal in the P-31 NMR spectra

Are the fusion processes involved in birth, life and death of the cell depending on tilted insertion of peptides into membranes?

Various peptide segments have been modeled as asymmetric amphipathic alpha-helices. Theoretical calculations have shown that they insert obliquely into model membranes. They have been named "tilted peptides". Molecular modeling results reported here also evidence the presence of tilted peptides in ADM-1 protein of Caenorhabditis elegans that may be involved in fusion events, in meltrin alpha, a protein implicated in myoblast fusion, in hemagglutinin of influenza virus, in the E2 glycoprotein of rubella virus, in the S protein of hepatitis B virus, in a subdomain of Ebola virus and in the malaria CS protein. Experimental results have indicated that tilted peptide fragments may be involved in cellular life events like sperm-egg fecondation, muscle development, protein translocation through signal sequences and cellular death caused by viral infection or parasite infestation. We speculate that membrane destabilization by these tilted peptides may be an important common step in life processes involving fusion phenomena. (C) 1999 Academic Press

Use of certain substituted pyrrolidones such as piracetam in the treatment of viral and other diseases

The invention concerns the use of certain pyrrolidone derivatives for the preparation of medicaments for the prevention and treatment of diseases caused by the tilted insertion of fusion peptides into cell membranes. It is particularly suitable for the prevention and treatment of viral diseases.info:eu-repo/semantics/publishe

Destabilization of a model membrane by a predicted fusion peptide of fertilin alpha

The subunit alpha of the guinea pig fertilin (previously known as PH-30, an integral membrane protein involved in sperm-egg binding and fusion) is predicted to be a potential fusion protein. The structure of this putative fusion protein was analysed by molecular modeling and we have found a peptidic sequence of 17 residues (D-83-P-99) organized in helix that inserts obliquely in lipid phases. The effect of this synthesized peptide was studied on a model membrane by P-31 NMR and light scattering, It appears to increase the size of lipid vesicles and induces structural modifications. We interpret these observations as a destabilization of the lipid organization by this peptide because of its tilted insertion in phospholipid layers. This destabilization could favor membrane fusion

Membrane Destabilization Induced By Beta-Amyloid Peptide 29-42: Importance Of The Amino-Terminus

Increasing evidence implicates interactions between Abeta-peptides and membrane lipids in Alzheimer's disease. To gain insight into the potential role of the free amino group of the N-terminus of Abeta29-42 fragment in these processes, we have investigated the ability of Abeta29-42 unprotected and Abeta29-42 N-protected to interact with negatively-charged liposomes and have calculated the interaction with membrane lipids by conformational analysis. Using vesicles mimicking the composition of neuronal membranes, we show that both peptides have a similar capacity to induce membrane fusion and permeabilization. The fusogenic effect is related to the appearance of non-bilayer structures where isotropic motions occur as shown by 31P and 2H NMR studies. The molecular modeling calculations confirm the experimental observations and suggest that lipid destabilization could be due to the ability of both peptides to adopt metastable positions in the presence of lipids. In conclusion, the presence of a free or protected (acetylated) amino group in the N-terminus of Abeta29-42 is therefore probably not crucial for destabilizing properties of the C-terminal fragment of Abeta peptides