The Cryo-EM structure of human CD163 bound to haptoglobin-hemoglobin reveals molecular mechanisms of hemoglobin scavenging

Anders Etzerodt, Jakob Hauge Mikkelsen, Morten Torvund-Jensen, Dorle Hennig, Thomas Boesen, Jonas Heilskov Graversen, Søren Kragh Moestrup, Justin M. Kollman and Christian Brix Folsted Andersen ()
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Anders Etzerodt: Aarhus University
Jakob Hauge Mikkelsen: Aarhus University
Morten Torvund-Jensen: Aarhus University
Dorle Hennig: University of Southern Denmark
Thomas Boesen: Aarhus University
Jonas Heilskov Graversen: University of Southern Denmark
Søren Kragh Moestrup: Aarhus University
Justin M. Kollman: University of Washington
Christian Brix Folsted Andersen: Aarhus University

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract CD163, a macrophage-specific receptor, plays a critical role in scavenging hemoglobin released during hemolysis, protecting against oxidative effects of heme iron. In the bloodstream, hemoglobin is bound by haptoglobin, leading to its immediate endocytosis by CD163. While haptoglobin’s structure and function are well understood, CD163’s structure and its interaction with the haptoglobin-hemoglobin complex have remained elusive. Here, we present the cryo-electron microscopy structure of the entire extracellular domain of human CD163 in complex with haptoglobin-hemoglobin. The structure reveals that CD163 assembles into trimers (and to some extent dimers), binding haptoglobin-hemoglobin in their center. Key acidic residues in CD163 interact with lysine residues from both haptoglobin and hemoglobin. Calcium-binding sites located near the haptoglobin-hemoglobin interface in CD163 provide explanation for the calcium dependence of the interaction. Furthermore, we show that the interaction facilitating CD163 oligomerization mimics ligand binding and is also calcium dependent. This structural insight into CD163 advances our understanding of its role in hemoglobin scavenging as well as its broader relevance to structurally related scavenger receptors.

Date: 2024
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DOI: 10.1038/s41467-024-55171-4

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