title: A single amino acid substitution in the group 1 Trypanosoma brucei gambiense haptoglobin-hemoglobin receptor abolishes TLF-1 binding.
abstract: Critical to human innate immunity against African trypanosomes is a minor subclass of human high-density lipoproteins, termed Trypanosome Lytic Factor-1 (TLF-1). This primate-specific molecule binds to a haptoglobin-hemoglobin receptor (HpHbR) on the surface of susceptible trypanosomes, initiating a lytic pathway. Group 1 Trypanosoma brucei gambiense causes human African Trypanosomiasis (HAT), escaping TLF-1 killing due to reduced uptake. Previously, we found that group 1 T. b. gambiense HpHbR (TbgHpHbR) mRNA levels were greatly reduced and the gene contained substitutions within the open reading frame. Here we show that a single, highly conserved amino acid in the TbgHpHbR ablates high affinity TLF-1 binding and subsequent endocytosis, thus evading TLF-1 killing. In addition, we show that over-expression of TbgHpHbR failed to rescue TLF-1 susceptibility. These findings suggest that the single substitution present in the TbgHpHbR directly contributes to the reduced uptake and resistance to TLF-1 seen in these important human pathogens.
authors: Department of Biochemistry and Molecular Biology, University of Georgia, Athens, Georgia, USA.
authors: E
authors: E
authors: DeJesus
authors: R
authors: R
authors: Kieft
authors: B
authors: B
authors: Albright
authors: N A
authors: NA
authors: Stephens
authors: S L
authors: SL
authors: Hajduk
mesh_terms: D019943:Amino Acid Substitution; D002460:Cell Line; D004705:Endocytosis; D055786:Gene Knockout Techniques; D006242:Haptoglobins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006454:Hemoglobins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D016415:Sequence Alignment; D014347:Trypanosoma brucei gambiense / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016833:Trypanosoma brucei rhodesiense / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014353:Trypanosomiasis, African / Q000276:immunology
chemical_list: D006242:Haptoglobins; D006454:Hemoglobins; D008075:Lipoproteins, HDL; C434063:TLF1 protein, human; C035492:haptoglobin-hemoglobin complex
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