title: Human haptoglobin structure and function--a molecular modelling study.
abstract: Hemoglobin is the most prominent protein in blood, transporting O(2) and facilitating reactive oxygen and nitrogen species detoxification. Hemoglobin metabolism leads to the release of extra-erythrocytic hemoglobin, with potentially severe consequences for health. Extra-erythrocytic hemoglobin is complexed to haptoglobin for clearance by tissue macrophages. The human gene for haptoglobin consists of three structural alleles: Hp1F, Hp1S and Hp2. The products of the Hp1F and Hp1S alleles differ by only one amino acid, whereas the Hp2 allele is the result of a fusion of the Hp1F and Hp1S alleles, is present only in humans and gives rise to a longer alpha-chain. Haptoglobin consists of a dimer of alphabeta-chains covalently linked by a disulphide bond between the Cys15 residue of each alpha-chain. However, the presence of the Hp1 and Hp2 alleles in humans gives rise to HPT1-1 dimers (covalently linked by Cys15 residues), HPT1-2 hetero-oligomers and HPT2-2 oligomers. In fact, the HPT2 variant displays two free Cys residues (Cys15 and Cys74) whose participation in intermolecular disulphide bonds gives rise to higher-order covalent multimers. Here, the complete modelling of both haptoglobin variants, together with their basic quaternary structure arrangements (i.e. HPT1 dimer and HPT2 trimer), is reported. The structural details of the models, which represent the first complete view of the molecular details of human haptoglobin variants, are discussed in relation to the known haptoglobin function(s).
authors.affiliation: Department of Biology and Interdepartmental Laboratory for Electron Microscopy, University Roma Tre, Italy. polticel@uniroma3.it
authors.forename: F
authors.initials: F
authors.lastname: Polticelli
authors.forename: A
authors.initials: A
authors.lastname: Bocedi
authors.forename: G
authors.initials: G
authors.lastname: Minervini
authors.forename: P
authors.initials: P
authors.lastname: Ascenzi
mesh_terms: D000483:Alleles; D019281:Dimerization; D014644:Genetic Variation; D006242:Haptoglobins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008958:Models, Molecular; D020836:Protein Structure, Quaternary
chemical_list: C485359:HP protein, human; D006242:Haptoglobins