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