Abstract
In mammals, haptoglobin (Hp) is an acute-phase plasma protein that binds with high affinity to hemoglobin (Hb) released by intravascular hemolysis. The resultant Hp-Hb complexes are bound and cleared by the scavenger receptor CD163, limiting Hb-induced oxidative damage. In this study, we show that Hp is a divergent member of the complement-initiating MASP family of proteins, which emerged in the ancestor of jawed vertebrates. We demonstrate that Hp has been independently lost from multiple vertebrate lineages, that characterized Hb-interacting residues of mammals are poorly conserved in nonmammalian species maintaining Hp, and that the extended loop 3 region of Hp, which mediates CD163 binding, is present only in mammals. We show that the Hb-binding ability of cartilaginous fish (nurse shark, Ginglymostoma cirratum; small-spotted catshark, Scyliorhinus canicula; and thornback ray, Raja clavata) and teleost fish (rainbow trout, Oncorhynchus mykiss) Hp is species specific, and where binding does occur it is likely mediated through a different structural mechanism to mammalian Hp. The continued, high-level expression of Hp in cartilaginous fishes in which Hb binding is not evident signals that Hp has (an)other, yet unstudied, role(s) in these species. Previous work indicates that mammalian Hp also has secondary, immunomodulatory functions that are independent of Hb binding; our work suggests these may be remnants of evolutionary more ancient functions, retained after Hb removal became the primary role of Hp in mammals.
Original language | English |
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Pages (from-to) | 2483-2491 |
Number of pages | 9 |
Journal | The Journal of Immunology |
Volume | 201 |
Issue number | 8 |
Early online date | 7 Sept 2018 |
DOIs | |
Publication status | Published - 15 Oct 2018 |
Bibliographical note
This work was supported by National Institutes of Health Grant RR06603 awarded to M.F.F., Royal Society Research Grant RG130789 awarded to H.D., and a Ph.D.studentship awarded by the Centre for Genome-Enabled Biology and Medicine,
University of Aberdeen, to A.K.R.
The sequences presented in this article have been submitted to GenBank under
accession numbers HM566086, JN564036, and MG747494.
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