Abstract
The adverse effects of extra-erythrocytic hemoglobin (Hb) are counterbalanced by several plasma proteins devoted to facilitate the clearance of free heme and Hb. In particular, haptoglobin (Hp) traps the αβ dimers of Hb, which are delivered to the reticulo-endothelial system by CD163 receptor-mediated endocytosis. Since Hp:Hb complexes show heme-based reactivity, kinetics of O2 dissociation from the ferrous oxygenated human Hp1-1:Hb and Hp2-2:Hb complexes (Hp1-1:Hb(II)-O2 and Hp2-2:Hb(II)-O2, respectively) have been determined. O2 dissociation from Hp1-1:Hb(II)-O2 and Hp2-2:Hb(III)-O2 follows a biphasic process. The relative amplitude of the fast and slow phases ranges between 0.47 and 0.53 of the total amplitude, with values of koff1 (ranging between 25.6 ± 1.4 s−1 and 29.1 ± 1.3 s−1) being about twice faster than those of koff2 (ranging between 13.8 ± 1.6 s−1 and 16.1 ± 1.2 s−1). Values of koff1 and koff2 are essentially the same independently on whether O2 dissociation has been followed after addition of a dithionite solution or after O2 displacement by a CO solution in the presence of dithionite. They correspond to those reported for the dissociation of the first O2 molecule from tetrameric Hb(II)-O2, indicating that in the R-state α and β chains are functionally heterogeneous and the tetramer and the dimer behave identically. Accordingly, the structural conformation of the α and β chains of the Hb dimer bound to Hp corresponds to that of the subunits of the Hb tetramer in the R-state.
Highlights
O2 molecule from tetrameric Hb(II)-O2, indicating that in the R-state α and β chains are functionally heterogeneous and the tetramer and the dimer behave identically
Www.nature.com/scientificreports hemopexin ensure the complete clearance of the free heme, which is released into hepatic parenchymal cells by the CD91 receptor-mediated endocytosis of the hemopexin-heme complex
By CD163 receptor-mediated endocytosis, the Hp:Hb complexes are delivered to the reticulo-endothelial system where they are degraded to release the heme
Summary
Received: 31 December 2018 Accepted: 15 April 2019 Published: xx xx xxxx complexes confirms that in the R-state α and β chains are functionally heterogeneous. As the Hp:Hb complexes show functional properties similar to those of the Hb R-state, e.g. they display a high ligand specificity and show neither “heme-heme interactions” nor the Bohr effect[30,31,32,33,34,35,36,37], we decided to investigate the kinetics of O2 dissociation from human Hb(II)-O2 dimers bound to human Hp phenotypes 1-1 and 2-2 (Hp11:Hb(II)-O2 and Hp2-2:Hb(II)-O2, respectively). All chemicals were of analytical grade and were used without further purification
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