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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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A comparison of the dimensions of the TbHpHbR:HpHb complex with those ofthe N-terminal domains of the variant surface glycoproteins (shown ingrey).This suggests that HpHb will lie at least partially within the VSG layer whenbound to two receptors.DOI:http://dx.doi.org/10.7554/eLife.05553.020
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fig5: A comparison of the dimensions of the TbHpHbR:HpHb complex with those ofthe N-terminal domains of the variant surface glycoproteins (shown ingrey).This suggests that HpHb will lie at least partially within the VSG layer whenbound to two receptors.DOI:http://dx.doi.org/10.7554/eLife.05553.020

Mentions: The precise nature of the integration of TbHpHbR into the VSG layer remains unresolvedas the effect of the C-terminal domains of both the receptor and VSG on the verticaldisposition of each molecule remains unknown. An attractive model is that the ligand,whether HpHb or TLF1, is bound above the top of the VSG. However, the dimensions of thestructures of VSG and the TbHpHbR:HpHb complex suggest that this may not be the case andthat the HpHb ligand is held at least partially within the VSG layer (Figure 5). The TLF1 ligand is ∼4 times thesize of HpHb and this must, at least partially, protrude above the top of the VSG layer.10.7554/eLife.05553.020Figure 5.A comparison of the dimensions of the TbHpHbR:HpHb complex with those ofthe N-terminal domains of the variant surface glycoproteins (shown ingrey).


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)

A comparison of the dimensions of the TbHpHbR:HpHb complex with those ofthe N-terminal domains of the variant surface glycoproteins (shown ingrey).This suggests that HpHb will lie at least partially within the VSG layer whenbound to two receptors.DOI:http://dx.doi.org/10.7554/eLife.05553.020
© Copyright Policy
Related In: Results  -  Collection

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

fig5: A comparison of the dimensions of the TbHpHbR:HpHb complex with those ofthe N-terminal domains of the variant surface glycoproteins (shown ingrey).This suggests that HpHb will lie at least partially within the VSG layer whenbound to two receptors.DOI:http://dx.doi.org/10.7554/eLife.05553.020
Mentions: The precise nature of the integration of TbHpHbR into the VSG layer remains unresolvedas the effect of the C-terminal domains of both the receptor and VSG on the verticaldisposition of each molecule remains unknown. An attractive model is that the ligand,whether HpHb or TLF1, is bound above the top of the VSG. However, the dimensions of thestructures of VSG and the TbHpHbR:HpHb complex suggest that this may not be the case andthat the HpHb ligand is held at least partially within the VSG layer (Figure 5). The TLF1 ligand is ∼4 times thesize of HpHb and this must, at least partially, protrude above the top of the VSG layer.10.7554/eLife.05553.020Figure 5.A comparison of the dimensions of the TbHpHbR:HpHb complex with those ofthe N-terminal domains of the variant surface glycoproteins (shown ingrey).

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