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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 .

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