Reference : C-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/2268/65876
C-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense.
English
Lecordier, Laurence [> > > >]
Vanhollebeke, Benoit [> > > >]
Poelvoorde, Philippe [> > > >]
Tebabi, Patricia [> > > >]
Paturiaux-Hanocq, Francoise [> > > >]
Andris, Fabienne [> > > >]
Lins, Laurence mailto [Université de Liège - ULg > Chimie et bio-industries > Centre de Bio. Fond. - Section de Biologie moléc. et numér. >]
Pays, Etienne [> > > >]
2009
PLoS Pathogens
Public Library of Science
5
12
e1000685
Yes
International
1553-7366
1553-7374
[en] Amino Acid Sequence ; Animals ; Apolipoproteins/genetics/metabolism/pharmacology/physiology ; Cell Survival/drug effects ; DNA Mutational Analysis ; Humans ; Leucine Zippers/genetics ; Lipoproteins, HDL/genetics/metabolism/pharmacology/physiology ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Transgenic ; Molecular Sequence Data ; Mutation ; Papio anubis ; Pore Forming Cytotoxic Proteins/genetics/metabolism/pharmacology ; Protein Binding ; Protozoan Proteins/metabolism ; Sequence Alignment ; Thermodynamics ; Trypanocidal Agents/metabolism/pharmacology ; Trypanosoma brucei brucei/metabolism/physiology ; Trypanosoma brucei rhodesiense/metabolism/physiology
[en] Apolipoprotein L-I (apoL1) is a human-specific serum protein that kills Trypanosoma brucei through ionic pore formation in endosomal membranes of the parasite. The T. brucei subspecies rhodesiense and gambiense resist this lytic activity and can infect humans, causing sleeping sickness. In the case of T. b. rhodesiense, resistance to lysis involves interaction of the Serum Resistance-Associated (SRA) protein with the C-terminal helix of apoL1. We undertook a mutational and deletional analysis of the C-terminal helix of apoL1 to investigate the linkage between interaction with SRA and lytic potential for different T. brucei subspecies. We confirm that the C-terminal helix is the SRA-interacting domain. Although in E. coli this domain was dispensable for ionic pore-forming activity, its interaction with SRA resulted in inhibition of this activity. Different mutations affecting the C-terminal helix reduced the interaction of apoL1 with SRA. However, mutants in the L370-L392 leucine zipper also lost in vitro trypanolytic activity. Truncating and/or mutating the C-terminal sequence of human apoL1 like that of apoL1-like sequences of Papio anubis resulted in both loss of interaction with SRA and acquired ability to efficiently kill human serum-resistant T. b. rhodesiense parasites, in vitro as well as in transgenic mice. These findings demonstrate that SRA interaction with the C-terminal helix of apoL1 inhibits its pore-forming activity and determines resistance of T. b. rhodesiense to human serum. In addition, they provide a possible explanation for the ability of Papio serum to kill T. b. rhodesiense, and offer a perspective to generate transgenic cattle resistant to both T. b. brucei and T. b. rhodesiense.
Researchers ; Professionals
http://hdl.handle.net/2268/65876
10.1371/journal.ppat.1000685

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