Haptoglobin-related protein mediates trypanosome lytic factor binding to trypanosomes.
Trypanosome lytic factor (TLF-1) is an unusual high density lipoprotein (HDL) found in human serum that is toxic to Trypanosoma brucei brucei and may be critical in preventing human infections by this parasite. TLF-1 is composed of four major apolipoproteins: apolipoprotein AI, apolipoprotein AII, paraoxonase, and the primate-specific haptoglobin-related protein (Hpr). Hpr is greater than 90% homologous to haptoglobin (Hp), an abundant acute phase serum protein. Killing of trypanosomes by TLF-1 requires cell surface binding, endocytosis, and subsequent lysosomal targeting. Low temperature binding studies reveal two receptors for TLF-1: one that is high affinity/low capacity (K(d) approximately 12 nm, 350 receptors per cell) and another that binds with low affinity/high capacity (K(d) approximately 1 microm, 60,000 receptors per cell). The low affinity binding is competed by nonlytic human HDL and is likely to be apolipoprotein AI-mediated. Purified human Hpr and human Hp bind to trypanosomes, are internalized, and are targeted to the lysosome. Furthermore, Hpr shows competition for TLF-1 binding, and a monoclonal antibody against Hpr prevents both TLF-1 uptake and trypanosome killing. Based on these results, we propose that Hpr mediates the high affinity binding of TLF-1 to T. b. brucei through a haptoglobin-like receptor.
Drain
J
J
Department of Biochemistry and Molecular Genetics, School of Medicine, University of Alabama at Birmingham, 35294, USA.
Bishop
J R
JR
Hajduk
S L
SL
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D000951:Antigens, Neoplasm; D001053:Apolipoproteins / Q000737:chemistry; D001667:Binding, Competitive; D001798:Blood Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D006242:Haptoglobins; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008856:Microscopy, Fluorescence; D011485:Protein Binding; D013696:Temperature; D014346:Trypanosoma brucei brucei / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D001053:Apolipoproteins; D001798:Blood Proteins; C058632:HPR protein, human; D006242:Haptoglobins; D008024:Ligands; D008075:Lipoproteins, HDL; C434063:TLF1 protein, human