Article (Scientific journals)
C-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense.
Lecordier, Laurence; Vanhollebeke, Benoit; Poelvoorde, Philippe et al.
2009In PLoS Pathogens, 5 (12), p. 1000685
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Keywords :
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
Abstract :
[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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Lecordier, Laurence
Vanhollebeke, Benoit
Poelvoorde, Philippe
Tebabi, Patricia
Paturiaux-Hanocq, Francoise
Andris, Fabienne
Lins, Laurence  ;  Université de Liège - ULiège > Chimie et bio-industries > Centre de Bio. Fond. - Section de Biologie moléc. et numér.
Pays, Etienne
Language :
English
Title :
C-terminal mutants of apolipoprotein L-I efficiently kill both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense.
Publication date :
2009
Journal title :
PLoS Pathogens
ISSN :
1553-7366
eISSN :
1553-7374
Publisher :
Public Library of Science
Volume :
5
Issue :
12
Pages :
e1000685
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 08 July 2010

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