title: Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system.
abstract: Sleeping sickness is caused by trypanosome parasites, which infect humans and livestock in Sub-Saharan Africa. Haem is an important growth factor for the parasites and is acquired from the host by receptor-mediated uptake of haptoglobin (Hp)-haemoglobin (Hb) complexes. The parasite Hp-Hb receptor (HpHbR) is also a target for a specialized innate immune defence executed by trypanosome-killing lipoprotein particles containing an Hp-related protein in complex with Hb. Here we report the structure of the multimeric complex between human Hp-Hb and Trypanosoma brucei brucei HpHbR. Two receptors forming kinked three-helical rods with small head regions bind to Hp and the β-subunits of Hb (βHb), with one receptor at each end of the dimeric Hp-Hb complex. The Hb β-subunit haem group directly associates with the receptors, which allows for sensing of haem-containing Hp-Hb. The HpHbR-binding region of Hp is conserved in Hp-related protein, indicating an identical recognition of Hp-Hb and trypanolytic particles by HpHbR in human plasma.
authors.affiliation: Department of Biomedicine, Aarhus University, Ole Worms Allé 3, DK-8000 Aarhus C, Denmark.
authors.forename: Kristian
authors.initials: K
authors.lastname: Stødkilde
authors.affiliation: Department of Biomedicine, Aarhus University, Ole Worms Allé 3, DK-8000 Aarhus C, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Torvund-Jensen
authors.affiliation: Department of Biomedicine, Aarhus University, Ole Worms Allé 3, DK-8000 Aarhus C, Denmark.
authors.forename: Søren K
authors.initials: SK
authors.lastname: Moestrup
authors.affiliation: Department of Biomedicine, Aarhus University, Ole Worms Allé 3, DK-8000 Aarhus C, Denmark.
authors.forename: Christian B F
authors.initials: CB
authors.lastname: Andersen
mesh_terms: D006242:Haptoglobins / Q000378:metabolism*; D006418:Heme / Q000378:metabolism*; D006454:Hemoglobins / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000276:immunology / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D014346:Trypanosoma brucei brucei / Q000378:metabolism*
chemical_list: D006242:Haptoglobins; D006454:Hemoglobins; D015800:Protozoan Proteins; D011956:Receptors, Cell Surface; C027079:hemoglobin-haptoglobin receptor; D006418:Heme; C020622:hemoglobin B