C-Terminal Mutants of Apolipoprotein L-I Efficiently Kill Both Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense

PLoS Pathogens

Laurence Lins¹  Fabienne Andris²  Françoise Paturiaux-Hanocq³  Etienne Pays³  Laurence Lecordier³  Benoit Vanhollebeke³  Philippe Poelvoorde³  Patricia Tebabi³ 

[1] Centre de Biophysique Moléculaire Numérique, Université de Gembloux, Gembloux, Belgium;Laboratory of Animal Physiology, IBMM, Université Libre de Bruxelles, Gosselies, Belgium;Laboratory of Molecular Parasitology, IBMM, Université Libre de Bruxelles, Gosselies, Belgium

关键词: Trypanosoma;    Trypanosoma brucei gambiense;    Protein interactions;    Cloning;    Serum proteins;    Trypanosoma brucei;    Parasitic diseases;    Protein domains;   

DOI  :  10.1371/journal.ppat.1000685

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY