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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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The region affected by haptoglobin cleavage is not involved ininteraction with TbHpHbR.(A) The structures of the HpSPHb region of porcine HpHb(red) aligned to the equivalent region of human HpSPHb from the structureof the TbHpHbR:HpSPHb complex (yellow). The structures align with a rootmean square deviation of ∼0.5 Å. The major difference iscircled and lies around the site at which haptoglobin is cleaved during aprocessing event in the endoplasmic reticulum, which is disordered in theTbHpHbR:HpSPHb complex. (B) A structural alignment of theporcine HpSPHb structure onto the TbHpHbR:HpSPHb structure. The regionthat is structurally altered by cleavage is circled and is not involvedin contacts with the receptor. This is confirmed by surface plasmonresonance data (Figure 1—figuresupplement 1) which shows that TbHpHbR binds with similaraffinity to HpSPHb as to previously measured native, cleaved HpHb.DOI:http://dx.doi.org/10.7554/eLife.05553.012
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fig2s4: The region affected by haptoglobin cleavage is not involved ininteraction with TbHpHbR.(A) The structures of the HpSPHb region of porcine HpHb(red) aligned to the equivalent region of human HpSPHb from the structureof the TbHpHbR:HpSPHb complex (yellow). The structures align with a rootmean square deviation of ∼0.5 Å. The major difference iscircled and lies around the site at which haptoglobin is cleaved during aprocessing event in the endoplasmic reticulum, which is disordered in theTbHpHbR:HpSPHb complex. (B) A structural alignment of theporcine HpSPHb structure onto the TbHpHbR:HpSPHb structure. The regionthat is structurally altered by cleavage is circled and is not involvedin contacts with the receptor. This is confirmed by surface plasmonresonance data (Figure 1—figuresupplement 1) which shows that TbHpHbR binds with similaraffinity to HpSPHb as to previously measured native, cleaved HpHb.DOI:http://dx.doi.org/10.7554/eLife.05553.012

Mentions: The haptoglobin subunit also interacts with helix I of the receptor, through apredominantly hydrophobic contact, mediated by three loops that emerge from theC-terminal β-sheet of haptoglobin (Figure2B, Table 4). The structure ofhuman haptoglobin from this complex aligns with that from porcine Hp with a root meansquare deviation of just 0.5 Å and reveals no significant structural change onreceptor binding (Figure 2—figure supplement4). The alignment also confirms that the natural cleavage of Hp does notaffect TbHpHbR binding, as residues in the loop that contains the cleavage site arenot close to the 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)

The region affected by haptoglobin cleavage is not involved ininteraction with TbHpHbR.(A) The structures of the HpSPHb region of porcine HpHb(red) aligned to the equivalent region of human HpSPHb from the structureof the TbHpHbR:HpSPHb complex (yellow). The structures align with a rootmean square deviation of ∼0.5 Å. The major difference iscircled and lies around the site at which haptoglobin is cleaved during aprocessing event in the endoplasmic reticulum, which is disordered in theTbHpHbR:HpSPHb complex. (B) A structural alignment of theporcine HpSPHb structure onto the TbHpHbR:HpSPHb structure. The regionthat is structurally altered by cleavage is circled and is not involvedin contacts with the receptor. This is confirmed by surface plasmonresonance data (Figure 1—figuresupplement 1) which shows that TbHpHbR binds with similaraffinity to HpSPHb as to previously measured native, cleaved HpHb.DOI:http://dx.doi.org/10.7554/eLife.05553.012
© Copyright Policy
Related In: Results  -  Collection

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

fig2s4: The region affected by haptoglobin cleavage is not involved ininteraction with TbHpHbR.(A) The structures of the HpSPHb region of porcine HpHb(red) aligned to the equivalent region of human HpSPHb from the structureof the TbHpHbR:HpSPHb complex (yellow). The structures align with a rootmean square deviation of ∼0.5 Å. The major difference iscircled and lies around the site at which haptoglobin is cleaved during aprocessing event in the endoplasmic reticulum, which is disordered in theTbHpHbR:HpSPHb complex. (B) A structural alignment of theporcine HpSPHb structure onto the TbHpHbR:HpSPHb structure. The regionthat is structurally altered by cleavage is circled and is not involvedin contacts with the receptor. This is confirmed by surface plasmonresonance data (Figure 1—figuresupplement 1) which shows that TbHpHbR binds with similaraffinity to HpSPHb as to previously measured native, cleaved HpHb.DOI:http://dx.doi.org/10.7554/eLife.05553.012
Mentions: The haptoglobin subunit also interacts with helix I of the receptor, through apredominantly hydrophobic contact, mediated by three loops that emerge from theC-terminal β-sheet of haptoglobin (Figure2B, Table 4). The structure ofhuman haptoglobin from this complex aligns with that from porcine Hp with a root meansquare deviation of just 0.5 Å and reveals no significant structural change onreceptor binding (Figure 2—figure supplement4). The alignment also confirms that the natural cleavage of Hp does notaffect TbHpHbR binding, as residues in the loop that contains the cleavage site arenot close to the 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