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Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system

Author

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  • Kristian Stødkilde

    (Aarhus University)

  • Morten Torvund-Jensen

    (Aarhus University)

  • Søren K. Moestrup

    (Aarhus University)

  • Christian B. F. Andersen

    (Aarhus University)

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.

Suggested Citation

  • Kristian Stødkilde & Morten Torvund-Jensen & Søren K. Moestrup & Christian B. F. Andersen, 2014. "Structural basis for trypanosomal haem acquisition and susceptibility to the host innate immune system," Nature Communications, Nature, vol. 5(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6487
    DOI: 10.1038/ncomms6487
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    Cited by:

    1. Thomas J. Bateman & Megha Shah & Timothy Pham Ho & Hyejin Esther Shin & Chuxi Pan & Greg Harris & Jamie E. Fegan & Epshita A. Islam & Sang Kyun Ahn & Yogesh Hooda & Scott D. Gray-Owen & Wangxue Chen &, 2021. "A Slam-dependent hemophore contributes to heme acquisition in the bacterial pathogen Acinetobacter baumannii," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Hagen Sülzen & Jakub Began & Arun Dhillon & Sami Kereïche & Petr Pompach & Jitka Votrubova & Farnaz Zahedifard & Adriana Šubrtova & Marie Šafner & Martin Hubalek & Maaike Thompson & Martin Zoltner & S, 2023. "Cryo-EM structures of Trypanosoma brucei gambiense ISG65 with human complement C3 and C3b and their roles in alternative pathway restriction," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    3. Eva Horáková & Laurence Lecordier & Paula Cunha & Roman Sobotka & Piya Changmai & Catharina J. M. Langedijk & Jan Van Den Abbeele & Benoit Vanhollebeke & Julius Lukeš, 2022. "Heme-deficient metabolism and impaired cellular differentiation as an evolutionary trade-off for human infectivity in Trypanosoma brucei gambiense," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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