4F4O

Structure of the Haptoglobin-Haemoglobin Complex

Summary for 4F4O

• Entry DOI: 10.2210/pdb4f4o/pdb
• Descriptor: Hemoglobin subunit alpha, Hemoglobin subunit beta, Haptoglobin, ... (8 entities in total)
• Functional Keywords: globin fold, serine protease fold, complement control protein, haemoglobin scavenging, oxygen storage-transport complex, oxygen transport-transport protein complex, oxygen transport/transport protein
• Biological source: Sus scrofa (pigs,swine,wild boar); More
• Total number of polymer chains: 12
• Total formula weight: 288309.26

Authors

Andersen, C.B.F.,Torvund-Jensen, M.,Nielsen, M.J.,Oliveira, C.L.P.,Hersleth, H.P.,Andersen, N.H.,Pedersen, J.S.,Andersen, G.R.,Moestrup, S.K. (deposition date: 2012-05-11, release date: 2012-08-29, Last modification date: 2024-10-09)

Primary citation

Andersen, C.B.,Torvund-Jensen, M.,Nielsen, M.J.,de Oliveira, C.L.,Hersleth, H.P.,Andersen, N.H.,Pedersen, J.S.,Andersen, G.R.,Moestrup, S.K.
Structure of the haptoglobin-haemoglobin complex.
Nature, 489:456-459, 2012

PubMed 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 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).

PubMed: 22922649
DOI: 10.1038/nature11369

Experimental method

X-RAY DIFFRACTION (2.9 Å)