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Structural basis for ligand and innate immunity factor uptake by the trypanosome haptoglobin-haemoglobin receptor.

Lane-Serff H, MacGregor P, Lowe ED, Carrington M, Higgins MK - Elife (2014)

Bottom Line: Lateral mobility of the glycosylphosphatidylinositol-anchored HpHbR, and a ∼50° kink in the receptor, allows two receptors to simultaneously bind one HpHb dimer.Indeed, trypanosomes take up dimeric HpHb at significantly lower concentrations than monomeric HpHb, due to increased ligand avidity that comes from bivalent binding.The structure therefore reveals the molecular basis for ligand and innate immunity factor uptake by trypanosomes and identifies adaptations that allow efficient ligand uptake in the context of the complex trypanosome cell surface.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

ABSTRACT
The haptoglobin-haemoglobin receptor (HpHbR) of African trypanosomes allows acquisition of haem and provides an uptake route for trypanolytic factor-1, a mediator of innate immunity against trypanosome infection. In this study, we report the structure of Trypanosoma brucei HpHbR in complex with human haptoglobin-haemoglobin (HpHb), revealing an elongated ligand-binding site that extends along its membrane distal half. This contacts haptoglobin and the β-subunit of haemoglobin, showing how the receptor selectively binds HpHb over individual components. Lateral mobility of the glycosylphosphatidylinositol-anchored HpHbR, and a ∼50° kink in the receptor, allows two receptors to simultaneously bind one HpHb dimer. Indeed, trypanosomes take up dimeric HpHb at significantly lower concentrations than monomeric HpHb, due to increased ligand avidity that comes from bivalent binding. The structure therefore reveals the molecular basis for ligand and innate immunity factor uptake by trypanosomes and identifies adaptations that allow efficient ligand uptake in the context of the complex trypanosome cell surface.

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Stereoview of the TbHpHbR in complex with HpHb.DOI:http://dx.doi.org/10.7554/eLife.05553.009
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fig2s1: Stereoview of the TbHpHbR in complex with HpHb.DOI:http://dx.doi.org/10.7554/eLife.05553.009

Mentions: The structure of the TbHpHbR:HpSPHb complex reveals an unexpected binding mode inwhich the ligand-binding surface extends along more than half of the length of thereceptor (Figure 2, Figure 2—figure supplement 1). Residues previouslyidentified as playing a role in HpHb binding in TcHpHbR, such as S59 (Higgins et al., 2013), lie ∼35 Åfrom the membrane distal tip of the receptor and directly contact haemoglobin.However, this is the upper part of the binding site, with residues from haptoglobininteracting as far as 70 Å from the membrane distal tip. This arrangement isconfirmed by small angle x-ray scattering, with complexes of HpSPHb bound to eitherT. brucei or T. congolense receptors showing asimilar architecture to that observed in the crystal (Figure 2—figure supplement 2, Table 3).


Structural basis for ligand and innate immunity factor uptake by the trypanosome haptoglobin-haemoglobin receptor.

Lane-Serff H, MacGregor P, Lowe ED, Carrington M, Higgins MK - Elife (2014)

Stereoview of the TbHpHbR in complex with HpHb.DOI:http://dx.doi.org/10.7554/eLife.05553.009
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4383175&req=5

fig2s1: Stereoview of the TbHpHbR in complex with HpHb.DOI:http://dx.doi.org/10.7554/eLife.05553.009
Mentions: The structure of the TbHpHbR:HpSPHb complex reveals an unexpected binding mode inwhich the ligand-binding surface extends along more than half of the length of thereceptor (Figure 2, Figure 2—figure supplement 1). Residues previouslyidentified as playing a role in HpHb binding in TcHpHbR, such as S59 (Higgins et al., 2013), lie ∼35 Åfrom the membrane distal tip of the receptor and directly contact haemoglobin.However, this is the upper part of the binding site, with residues from haptoglobininteracting as far as 70 Å from the membrane distal tip. This arrangement isconfirmed by small angle x-ray scattering, with complexes of HpSPHb bound to eitherT. brucei or T. congolense receptors showing asimilar architecture to that observed in the crystal (Figure 2—figure supplement 2, Table 3).

Bottom Line: Lateral mobility of the glycosylphosphatidylinositol-anchored HpHbR, and a ∼50° kink in the receptor, allows two receptors to simultaneously bind one HpHb dimer.Indeed, trypanosomes take up dimeric HpHb at significantly lower concentrations than monomeric HpHb, due to increased ligand avidity that comes from bivalent binding.The structure therefore reveals the molecular basis for ligand and innate immunity factor uptake by trypanosomes and identifies adaptations that allow efficient ligand uptake in the context of the complex trypanosome cell surface.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

ABSTRACT
The haptoglobin-haemoglobin receptor (HpHbR) of African trypanosomes allows acquisition of haem and provides an uptake route for trypanolytic factor-1, a mediator of innate immunity against trypanosome infection. In this study, we report the structure of Trypanosoma brucei HpHbR in complex with human haptoglobin-haemoglobin (HpHb), revealing an elongated ligand-binding site that extends along its membrane distal half. This contacts haptoglobin and the β-subunit of haemoglobin, showing how the receptor selectively binds HpHb over individual components. Lateral mobility of the glycosylphosphatidylinositol-anchored HpHbR, and a ∼50° kink in the receptor, allows two receptors to simultaneously bind one HpHb dimer. Indeed, trypanosomes take up dimeric HpHb at significantly lower concentrations than monomeric HpHb, due to increased ligand avidity that comes from bivalent binding. The structure therefore reveals the molecular basis for ligand and innate immunity factor uptake by trypanosomes and identifies adaptations that allow efficient ligand uptake in the context of the complex trypanosome cell surface.

Show MeSH
Related in: MedlinePlus