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

Crowet, Jean-Marc; Lins, Laurence; Dupiereux-Fettweis, Ingrid; Elmoualij, Benaïssa; Lorin, Aurélien; Charloteaux, Benoît; Stroobant, Vincent; Heinen, Ernst; Brasseur, Robert

doi:10.1002/prot.21483

Article (Scientific journals)

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

Crowet, Jean-Marc; Lins, Laurence; Dupiereux-Fettweis, Ingrid et al.

2007 • In Proteins, 68 (4), p. 936-947

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https://hdl.handle.net/2268/23340

DOI
10.1002/prot.21483

PubMed
17554782

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Keywords :

Circular Dichroism; hydrophobicity; lipid-interacting peptides; molecular modelling; Neurotoxins/toxicity; Parkinson; Peptide Fragments/toxicity; Phospholipids; Stress, Mechanical; tilted peptides

Abstract :

[en] Alpha-synuclein is a 140 residue protein associated with Parkinson's disease. Intraneural inclusions called Lewy bodies and Lewy neurites are mainly composed of alpha-synuclein aggregated into amyloid fibrils. Other amyloidogenic proteins, such as the beta amyloid peptide involved in Alzheimer's disease and the prion protein (PrP) associated with Creuztfeldt-Jakob's 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 alpha-synuclein is a tilted peptide. Its destabilizing properties were tested experimentally. The alpha-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 alpha-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 alpha-synuclein, which could be involved in the toxicity induced during amyloidogenesis of alpha-synuclein.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Crowet, Jean-Marc

Lins, Laurence ; Université de Liège - ULiège > Chimie et bio-industries > Biophysique moléc. numér.

Dupiereux-Fettweis, Ingrid ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie humaine

Elmoualij, Benaïssa ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie humaine

Lorin, Aurélien

Charloteaux, Benoît ; Université de Liège - ULiège > Gembloux Agro-Bio Tech

Stroobant, Vincent

Heinen, Ernst ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Histologie humaine

Brasseur, Robert ; Université de Liège - ULiège > Gembloux Agro-Bio Tech

Language :

English

Title :

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

Publication date :

September 2007

Journal title :

Proteins

ISSN :

0887-3585

eISSN :

1097-0134

Publisher :

Wiley, Hoboken, United States - New York

Volume :

Issue :

Pages :

936-947

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

* Crowet Jean-Marc et Lins Laurence 1er co-auteurs

Available on ORBi :

since 22 September 2009

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