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Haptoglobin, a hemoglobin-binding plasma protein, is present in bony fish and mammals but not in frog and chicken
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2006 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 103, no 11, 4168-4173 p.Article in journal (Refereed) Published
Abstract [en]

Hemoglobin (Hb) released from erythrocytes may cause oxidation of lipids and proteins. Haptoglobin (Hp), which occurs in the plasma of all mammals, binds free Hb and inhibits its oxidative activity. It is not known whether this protective protein also exists in lower vertebrates. By analyzing available genomic sequences, we have found that bony fish, but not more primitive animals, have a gene coding for a protein homologous to mammalian Hp. Furthermore, we show that this protein is present in the plasma of Japanese pufferfish (Takifugu rubripes) and that it binds Hb. These results, together with a phylogenetic analysis, suggest that Hp evolved from a complement-associated protein (mannose-binding lectin-associated serine proteinase, MASP), with the emergence of fish. Surprisingly, we found that both chicken (Gallus gallus) and the Western clawed frog (Xenopus tropicalis) lack the Hp gene. In chicken plasma, however, we identified a different type of Hb-binding protein, PIT54, which has been reported to be a potent antioxidant. PIT54 is a soluble member of the family of scavenger receptor cysteine-rich proteins, and we found that its gene exists only in birds. We also show that the plasma of ostrich (Strutio camelus), a primitive bird, contains both PIT54 and Hp. Collectively, our data suggest that PIT54 has successively taken over the function of Hp during the evolution of the avian lineage and has completely replaced the latter protein in chicken.

Place, publisher, year, edition, pages
2006. Vol. 103, no 11, 4168-4173 p.
Keyword [en]
Amino Acid Sequence, Animals, Birds/genetics, Chickens/genetics, Chromosome Mapping, Evolution; Molecular, Fishes/genetics, Haptoglobins/*genetics, Humans, Invertebrates/genetics, Mammals/genetics, Molecular Sequence Data, Phylogeny, Sequence Homology; Amino Acid, Species Specificity, Xenopus/genetics
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-94049DOI: 10.1073/pnas.0508723103PubMedID: 16537503OAI: oai:DiVA.org:uu-94049DiVA: diva2:167757
Available from: 2006-02-28 Created: 2006-02-28 Last updated: 2013-05-23Bibliographically approved
In thesis
1. Haptoglobin: Biosynthesis and Evolution
Open this publication in new window or tab >>Haptoglobin: Biosynthesis and Evolution
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Haptoglobin (Hp) is a serum protein known for its ability to form a tight complex with hemoglobin (Hb) and thereby inhibiting the oxidative activity of Hb.

Mammalian Hp is synthesized as a precursor (proHp) that undergoes proteolytic cleavage by a previously unidentified enzyme in the endoplasmic reticulum (ER). In this study, a proHp-cleaving enzyme was isolated from human serum and identified as complement C1r-like protein (C1rLP). Co-expression of C1rLP with proHp in mammalian cells resulted in cleavage of the latter protein in the ER. Mutation of either the active site serine residue in C1rLP or the arginine residue in the cleavage site of Hp abolished the cleavage of proHp by C1rLP. RNAi studies in mammalian cells identified the proHp-cleaving enzyme as C1rLP.

Hp has been found in all mammals studied to date but its presence in non-mammalian species has not been unambiguously shown. By searching currently available genomic DNA and cDNA sequence databases, a gene orthologous to mammalian Hp was found in bony fish. Hp-like protein expressed from this gene was demonstrated to be a major Hb protein in fish serum. Surprisingly, no Hp-like gene was found in the genomes of either frog or chicken. In chicken, a protein previously described as Hp was identified as PIT54, a member of a scavenger receptor cysteine-rich family of proteins. Interestingly, ostrich serum seemed to contain two Hb-binding proteins; one similar to PIT54 and one to mammalian Hp. We are not aware of any other case where the function of one gene has been taken over by another, completely unrelated gene

Fish Hp (fHp) is composed of a serine proteinase-related domain preceded by an extension consisting of several aminoa acids and a signal peptide. The extension contains a consensus motif for cleavage by subtilisin-like proprotein convertases (SPCs). fHp was found to be cleaved by SPCs in the Golgi complex.

Collectively, this thesis presents evidence that Hp has undergone significant changes during evolution with respect to its molecular organization and to the mechanism of its proteolytic cleavage.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 54 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 109
Molecular biology, haptoglobin, cleavage, C1r-LP, evolution, vertebrate, endoplasmic, Golgi, complement, Molekylärbiologi
National Category
Biochemistry and Molecular Biology
urn:nbn:se:uu:diva-6446 (URN)91-554-6470-X (ISBN)
Public defence
2006-03-21, Room C10:301, BMC, Husargatan 3, Uppsala, 12:30
Available from: 2006-02-28 Created: 2006-02-28Bibliographically approved

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