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  • 1
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    Structure of the haptoglobin-haemoglobin complex (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-08-28
    Description: 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 A resolution. This structure reveals that haptoglobin molecules dimerize through an unexpected beta-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 alpha- and beta-subunits of haemoglobin, explaining the tight binding between haptoglobin and haemoglobin. The haemoglobin-interacting region in the alphabeta dimer is highly overlapping with the interface between the two alphabeta 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 alpha-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).〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Andersen, Christian Brix Folsted -- Torvund-Jensen, Morten -- Nielsen, Marianne Jensby -- de Oliveira, Cristiano Luis Pinto -- Hersleth, Hans-Petter -- Andersen, Niels Hojmark -- Pedersen, Jan Skov -- Andersen, Gregers Rom -- Moestrup, Soren Kragh -- England -- Nature. 2012 Sep 20;489(7416):456-9. doi: 10.1038/nature11369. Epub 2012 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark. cbfa@biokemi.au.dk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22922649" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Binding Sites ; Complement C1r/chemistry ; Conserved Sequence ; Haptoglobins/*chemistry/metabolism ; Heme/chemistry ; Hemoglobins/*chemistry/metabolism ; Humans ; Models, Molecular ; Oxidation-Reduction ; Protein Multimerization ; Protein Structure, Quaternary ; Scattering, Small Angle ; Structure-Activity Relationship ; *Sus scrofa ; X-Ray Diffraction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Mechanism of Trypanosoma brucei gambiense resistance to human serum (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-08-24
    Description: The African parasite Trypanosoma brucei gambiense accounts for 97% of human sleeping sickness cases. T. b. gambiense resists the specific human innate immunity acting against several other tsetse-fly-transmitted trypanosome species such as T. b. brucei, the causative agent of nagana disease in cattle. Human immunity to some African trypanosomes is due to two serum complexes designated trypanolytic factors (TLF-1 and -2), which both contain haptoglobin-related protein (HPR) and apolipoprotein LI (APOL1). Whereas HPR association with haemoglobin (Hb) allows TLF-1 binding and uptake via the trypanosome receptor TbHpHbR (ref. 5), TLF-2 enters trypanosomes independently of TbHpHbR (refs 4, 5). APOL1 kills trypanosomes after insertion into endosomal/lysosomal membranes. Here we report that T. b. gambiense resists TLFs via a hydrophobic beta-sheet of the T. b. gambiense-specific glycoprotein (TgsGP), which prevents APOL1 toxicity and induces stiffening of membranes upon interaction with lipids. Two additional features contribute to resistance to TLFs: reduction of sensitivity to APOL1 requiring cysteine protease activity, and TbHpHbR inactivation due to a L210S substitution. According to such a multifactorial defence mechanism, transgenic expression of T. b. brucei TbHpHbR in T. b. gambiense did not cause parasite lysis in normal human serum. However, these transgenic parasites were killed in hypohaptoglobinaemic serum, after high TLF-1 uptake in the absence of haptoglobin (Hp) that competes for Hb and receptor binding. TbHpHbR inactivation preventing high APOL1 loading in hypohaptoglobinaemic serum may have evolved because of the overlapping endemic area of T. b. gambiense infection and malaria, the main cause of haemolysis-induced hypohaptoglobinaemia in western and central Africa.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Uzureau, Pierrick -- Uzureau, Sophie -- Lecordier, Laurence -- Fontaine, Frederic -- Tebabi, Patricia -- Homble, Fabrice -- Grelard, Axelle -- Zhendre, Vanessa -- Nolan, Derek P -- Lins, Laurence -- Crowet, Jean-Marc -- Pays, Annette -- Felu, Cecile -- Poelvoorde, Philippe -- Vanhollebeke, Benoit -- Moestrup, Soren K -- Lyngso, Jeppe -- Pedersen, Jan Skov -- Mottram, Jeremy C -- Dufourc, Erick J -- Perez-Morga, David -- Pays, Etienne -- 085349/Wellcome Trust/United Kingdom -- England -- Nature. 2013 Sep 19;501(7467):430-4. doi: 10.1038/nature12516. Epub 2013 Aug 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Parasitology, IBMM, Universite Libre de Bruxelles, 12 rue des Prof. Jeener et Brachet, B-6041 Gosselies, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23965626" target="_blank"〉PubMed〈/a〉
    Keywords: Africa ; Animals ; Animals, Genetically Modified ; Apolipoproteins/antagonists & inhibitors/*blood/*metabolism/toxicity ; Cell Membrane/chemistry/metabolism ; Cysteine Proteases/metabolism ; Haptoglobins/metabolism ; Hemoglobins/metabolism ; Hemolysis ; Humans ; Hydrophobic and Hydrophilic Interactions ; Lipid Metabolism ; Lipoproteins, HDL/antagonists & inhibitors/*blood/chemistry/*metabolism/toxicity ; Parasites/pathogenicity/physiology ; Protein Structure, Secondary ; Serum/chemistry/parasitology ; Trypanosoma brucei gambiense/drug effects/pathogenicity/*physiology ; Trypanosomiasis, African/parasitology ; Variant Surface Glycoproteins, Trypanosoma/chemistry/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    A haptoglobin-hemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans (2008)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2008-05-03
    Description: The protozoan parasite Trypanosoma brucei is lysed by apolipoprotein L-I, a component of human high-density lipoprotein (HDL) particles that are also characterized by the presence of haptoglobin-related protein. We report that this process is mediated by a parasite glycoprotein receptor, which binds the haptoglobin-hemoglobin complex with high affinity for the uptake and incorporation of heme into intracellular hemoproteins. In mice, this receptor was required for optimal parasite growth and the resistance of parasites to the oxidative burst by host macrophages. In humans, the trypanosome receptor also recognized the complex between hemoglobin and haptoglobin-related protein, which explains its ability to capture trypanolytic HDLs. Thus, in humans the presence of haptoglobin-related protein has diverted the function of the trypanosome haptoglobin-hemoglobin receptor to elicit innate host immunity against the parasite.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vanhollebeke, Benoit -- De Muylder, Geraldine -- Nielsen, Marianne J -- Pays, Annette -- Tebabi, Patricia -- Dieu, Marc -- Raes, Martine -- Moestrup, Soren K -- Pays, Etienne -- New York, N.Y. -- Science. 2008 May 2;320(5876):677-81. doi: 10.1126/science.1156296.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Parasitology, Institute for Molecular Biology and Medicine, Universite Libre de Bruxelles, 12 rue des Profs Jeener et Brachet, B6041 Gosselies, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18451305" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Haptoglobins/metabolism ; Hemoglobins/metabolism ; Humans ; Immunity, Innate ; Lipoproteins, HDL/metabolism ; Mice ; Mice, Inbred Strains ; Molecular Sequence Data ; Receptors, Cell Surface/*immunology/metabolism ; Trypanosoma brucei brucei/*immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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