Abstract
In hemolytic disorders, erythrocyte lysis results in massive release of hemoglobin and, subsequently, toxic heme. Hemopexin is the major protective factor against heme toxicity in human blood and currently considered for therapeutic use. It has been widely accepted that hemopexin binds heme with extraordinarily high affinity of <1 pM in a 1:1 ratio. However, several lines of evidence point to a higher stoichiometry and lower affinity than determined 50 years ago. Here, we re-analyzed these data. SPR and UV/Vis spectroscopy were used to monitor the interaction of heme with the human protein. The heme-binding sites of hemopexin were characterized using hemopexin-derived peptide models and competitive displacement assays. We obtained a KD value of 0.32 ± 0.04 nM and the ratio for the interaction was determined to be 1:1 at low heme concentrations and at least 2:1 (heme:hemopexin) at high concentrations. We were able to identify two yet unknown potential heme-binding sites on hemopexin. Furthermore, molecular modelling with a newly created homology model of human hemopexin suggested a possible recruiting mechanism by which heme could consecutively bind several histidine residues on its way into the binding pocket. Our findings have direct implications for the potential administration of hemopexin in hemolytic disorders.
Funding source: Leibniz-Gemeinschaft
Funding source: Rheinische Friedrich-Wilhelms-Universität Bonn
Funding source: Federal Government of Germany
Acknowledgements
The authors would like to thank Sabrina Linden (University of Bonn, Germany) for technical assistance. The authors would like to thank Britta Nubbemeyer for performing MS measurements. Financial support by the University of Bonn is gratefully acknowledged. The Leibniz-IPHT is member of the Leibniz Association and financially supported by the Federal Government of Germany and the State of Thuringia.
Author contributions: D.I. designed and planned the project. M.S.D, B.F.S., and D.I. conceived the study and workflow. M.S.D., M.-T.H., B.F.S., and A.R. performed the experiments and collected the data. M.S.D., B.F.S., A.A.P.G., M.-T.H., A.R., U.N., and D.I. analyzed the data. A.A.P.G. and F.S. performed the computational studies. The manuscript was written through the contribution of all authors.
Research funding: University of Bonn and Federal Government of Germany and State of Thuringia through the Leibniz Association.
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
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Supplementary Material
The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2020-0347).
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