Søren Kragh Moestrup

Structure of the haptoglobin-haemoglobin complex

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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Structure of the haptoglobin-haemoglobin complex. / Andersen, Christian Brix Folsted; Torvund-Jensen, Morten; Nielsen, Marianne Jensby; de Oliveira, Cristiano Luis Pinto; Hersleth, Hans-Petter; Andersen, Niels Højmark; Pedersen, Jan Skov; Andersen, Gregers Rom; Moestrup, Søren Kragh.

In: Nature, Vol. 489, No. 7416, 20.09.2012, p. 456-459.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Harvard

Andersen, CBF, Torvund-Jensen, M, Nielsen, MJ, de Oliveira, CLP, Hersleth, H-P, Andersen, NH, Pedersen, JS, Andersen, GR & Moestrup, SK 2012, 'Structure of the haptoglobin-haemoglobin complex', Nature, vol. 489, no. 7416, pp. 456-459. https://doi.org/10.1038/nature11369

APA

Andersen, C. B. F., Torvund-Jensen, M., Nielsen, M. J., de Oliveira, C. L. P., Hersleth, H-P., Andersen, N. H., Pedersen, J. S., Andersen, G. R., & Moestrup, S. K. (2012). Structure of the haptoglobin-haemoglobin complex. Nature, 489(7416), 456-459. https://doi.org/10.1038/nature11369

CBE

Andersen CBF, Torvund-Jensen M, Nielsen MJ, de Oliveira CLP, Hersleth H-P, Andersen NH, Pedersen JS, Andersen GR, Moestrup SK. 2012. Structure of the haptoglobin-haemoglobin complex. Nature. 489(7416):456-459. https://doi.org/10.1038/nature11369

MLA

Vancouver

Andersen CBF, Torvund-Jensen M, Nielsen MJ, de Oliveira CLP, Hersleth H-P, Andersen NH et al. Structure of the haptoglobin-haemoglobin complex. Nature. 2012 Sep 20;489(7416):456-459. https://doi.org/10.1038/nature11369

Author

Andersen, Christian Brix Folsted ; Torvund-Jensen, Morten ; Nielsen, Marianne Jensby ; de Oliveira, Cristiano Luis Pinto ; Hersleth, Hans-Petter ; Andersen, Niels Højmark ; Pedersen, Jan Skov ; Andersen, Gregers Rom ; Moestrup, Søren Kragh. / Structure of the haptoglobin-haemoglobin complex. In: Nature. 2012 ; Vol. 489, No. 7416. pp. 456-459.

Bibtex

@article{2598474982d04e73b7bc0ff3a59ba8e2,
title = "Structure of the haptoglobin-haemoglobin complex",
abstract = "Red cell haemoglobin is the fundamental oxygen-transporting molecule in blood, but also a potentially tissue-damaging compound owing to its highly reactive haem groups. During intravascular haemolysis, such as in malaria and haemoglobinopathies, haemoglobin is released into the plasma, where it is captured by the protective acute-phase protein haptoglobin. This leads to formation of the haptoglobin-haemoglobin complex, which represents a virtually irreversible non-covalent protein-protein interaction. Here we present the crystal structure of the dimeric porcine haptoglobin-haemoglobin complex determined at 2.9 {\AA} resolution. This structure reveals that haptoglobin molecules dimerize through an unexpected β-strand swap between two complement control protein (CCP) domains, defining a new fusion CCP domain structure. The haptoglobin serine protease domain forms extensive interactions with both the α- and β-subunits of haemoglobin, explaining the tight binding between haptoglobin and haemoglobin. The haemoglobin-interacting region in the αβ dimer is highly overlapping with the interface between the two αβ dimers that constitute the native haemoglobin tetramer. Several haemoglobin residues prone to oxidative modification after exposure to haem-induced reactive oxygen species are buried in the haptoglobin-haemoglobin interface, thus showing a direct protective role of haptoglobin. The haptoglobin loop previously shown to be essential for binding of haptoglobin-haemoglobin to the macrophage scavenger receptor CD163 (ref. 3) protrudes from the surface of the distal end of the complex, adjacent to the associated haemoglobin α-subunit. Small-angle X-ray scattering measurements of human haptoglobin-haemoglobin bound to the ligand-binding fragment of CD163 confirm receptor binding in this area, and show that the rigid dimeric complex can bind two receptors. Such receptor cross-linkage may facilitate scavenging and explain the increased functional affinity of multimeric haptoglobin-haemoglobin for CD163 (ref. 4).",
author = "Andersen, {Christian Brix Folsted} and Morten Torvund-Jensen and Nielsen, {Marianne Jensby} and {de Oliveira}, {Cristiano Luis Pinto} and Hans-Petter Hersleth and Andersen, {Niels H{\o}jmark} and Pedersen, {Jan Skov} and Andersen, {Gregers Rom} and Moestrup, {S{\o}ren Kragh}",
year = "2012",
month = sep,
day = "20",
doi = "10.1038/nature11369",
language = "English",
volume = "489",
pages = "456--459",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7416",

}

RIS

TY - JOUR

T1 - Structure of the haptoglobin-haemoglobin complex

AU - Andersen, Christian Brix Folsted

AU - Torvund-Jensen, Morten

AU - Nielsen, Marianne Jensby

AU - de Oliveira, Cristiano Luis Pinto

AU - Hersleth, Hans-Petter

AU - Andersen, Niels Højmark

AU - Pedersen, Jan Skov

AU - Andersen, Gregers Rom

AU - Moestrup, Søren Kragh

PY - 2012/9/20

Y1 - 2012/9/20

N2 - Red cell haemoglobin is the fundamental oxygen-transporting molecule in blood, but also a potentially tissue-damaging compound owing to its highly reactive haem groups. During intravascular haemolysis, such as in malaria and haemoglobinopathies, haemoglobin is released into the plasma, where it is captured by the protective acute-phase protein haptoglobin. This leads to formation of the haptoglobin-haemoglobin complex, which represents a virtually irreversible non-covalent protein-protein interaction. Here we present the crystal structure of the dimeric porcine haptoglobin-haemoglobin complex determined at 2.9 Å resolution. This structure reveals that haptoglobin molecules dimerize through an unexpected β-strand swap between two complement control protein (CCP) domains, defining a new fusion CCP domain structure. The haptoglobin serine protease domain forms extensive interactions with both the α- and β-subunits of haemoglobin, explaining the tight binding between haptoglobin and haemoglobin. The haemoglobin-interacting region in the αβ dimer is highly overlapping with the interface between the two αβ dimers that constitute the native haemoglobin tetramer. Several haemoglobin residues prone to oxidative modification after exposure to haem-induced reactive oxygen species are buried in the haptoglobin-haemoglobin interface, thus showing a direct protective role of haptoglobin. The haptoglobin loop previously shown to be essential for binding of haptoglobin-haemoglobin to the macrophage scavenger receptor CD163 (ref. 3) protrudes from the surface of the distal end of the complex, adjacent to the associated haemoglobin α-subunit. Small-angle X-ray scattering measurements of human haptoglobin-haemoglobin bound to the ligand-binding fragment of CD163 confirm receptor binding in this area, and show that the rigid dimeric complex can bind two receptors. Such receptor cross-linkage may facilitate scavenging and explain the increased functional affinity of multimeric haptoglobin-haemoglobin for CD163 (ref. 4).

AB - Red cell haemoglobin is the fundamental oxygen-transporting molecule in blood, but also a potentially tissue-damaging compound owing to its highly reactive haem groups. During intravascular haemolysis, such as in malaria and haemoglobinopathies, haemoglobin is released into the plasma, where it is captured by the protective acute-phase protein haptoglobin. This leads to formation of the haptoglobin-haemoglobin complex, which represents a virtually irreversible non-covalent protein-protein interaction. Here we present the crystal structure of the dimeric porcine haptoglobin-haemoglobin complex determined at 2.9 Å resolution. This structure reveals that haptoglobin molecules dimerize through an unexpected β-strand swap between two complement control protein (CCP) domains, defining a new fusion CCP domain structure. The haptoglobin serine protease domain forms extensive interactions with both the α- and β-subunits of haemoglobin, explaining the tight binding between haptoglobin and haemoglobin. The haemoglobin-interacting region in the αβ dimer is highly overlapping with the interface between the two αβ dimers that constitute the native haemoglobin tetramer. Several haemoglobin residues prone to oxidative modification after exposure to haem-induced reactive oxygen species are buried in the haptoglobin-haemoglobin interface, thus showing a direct protective role of haptoglobin. The haptoglobin loop previously shown to be essential for binding of haptoglobin-haemoglobin to the macrophage scavenger receptor CD163 (ref. 3) protrudes from the surface of the distal end of the complex, adjacent to the associated haemoglobin α-subunit. Small-angle X-ray scattering measurements of human haptoglobin-haemoglobin bound to the ligand-binding fragment of CD163 confirm receptor binding in this area, and show that the rigid dimeric complex can bind two receptors. Such receptor cross-linkage may facilitate scavenging and explain the increased functional affinity of multimeric haptoglobin-haemoglobin for CD163 (ref. 4).

U2 - 10.1038/nature11369

DO - 10.1038/nature11369

M3 - Journal article

C2 - 22922649

VL - 489

SP - 456

EP - 459

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7416

ER -