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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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Alignment of the TbHpHbR and TcHpHbR structures.Structural alignment of T. brucei HpHbR (blue) withT. congolense HpHbR (red). The membrane distal(upper) halves of the receptors align with a root mean square deviationof 1.1 Å while the membrane proximal (lower) halves differ due tothe presence of a ∼50° kink in TbHpHbR.DOI:http://dx.doi.org/10.7554/eLife.05553.007
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fig1s2: Alignment of the TbHpHbR and TcHpHbR structures.Structural alignment of T. brucei HpHbR (blue) withT. congolense HpHbR (red). The membrane distal(upper) halves of the receptors align with a root mean square deviationof 1.1 Å while the membrane proximal (lower) halves differ due tothe presence of a ∼50° kink in TbHpHbR.DOI:http://dx.doi.org/10.7554/eLife.05553.007

Mentions: Like T. congolense HpHbR, the T. brucei receptor iselongated, consisting primarily of a three-helical bundle (Figure 1): helix I (red; residues 42–110), helix II(orange; residues 116–182), and helix V (dark blue; residues 224–296)with a total length of 118 Å. At the membrane distal end, the receptor widens toform a compact head structure that includes the N-terminus and a 42-residue loopcontaining two further helices, helix III (yellow: residues 186–196) and helixIV (green: residues 207-–218). The upper part of the structure is extremelysimilar to that from T. congolense, with the membrane distal halvesof the two receptors aligning with a root mean square deviation of 1.1 Å (Figure 1—figure supplement 2).10.7554/eLife.05553.005Figure 1.The structure of the T. bruceihaptoglobin-haemoglobin receptor.


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)

Alignment of the TbHpHbR and TcHpHbR structures.Structural alignment of T. brucei HpHbR (blue) withT. congolense HpHbR (red). The membrane distal(upper) halves of the receptors align with a root mean square deviationof 1.1 Å while the membrane proximal (lower) halves differ due tothe presence of a ∼50° kink in TbHpHbR.DOI:http://dx.doi.org/10.7554/eLife.05553.007
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4383175&req=5

fig1s2: Alignment of the TbHpHbR and TcHpHbR structures.Structural alignment of T. brucei HpHbR (blue) withT. congolense HpHbR (red). The membrane distal(upper) halves of the receptors align with a root mean square deviationof 1.1 Å while the membrane proximal (lower) halves differ due tothe presence of a ∼50° kink in TbHpHbR.DOI:http://dx.doi.org/10.7554/eLife.05553.007
Mentions: Like T. congolense HpHbR, the T. brucei receptor iselongated, consisting primarily of a three-helical bundle (Figure 1): helix I (red; residues 42–110), helix II(orange; residues 116–182), and helix V (dark blue; residues 224–296)with a total length of 118 Å. At the membrane distal end, the receptor widens toform a compact head structure that includes the N-terminus and a 42-residue loopcontaining two further helices, helix III (yellow: residues 186–196) and helixIV (green: residues 207-–218). The upper part of the structure is extremelysimilar to that from T. congolense, with the membrane distal halvesof the two receptors aligning with a root mean square deviation of 1.1 Å (Figure 1—figure supplement 2).10.7554/eLife.05553.005Figure 1.The structure of the T. bruceihaptoglobin-haemoglobin receptor.

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