TY - JOUR
T1 - The Cryo-EM structure of human CD163 bound to haptoglobin-hemoglobin reveals molecular mechanisms of hemoglobin scavenging
AU - Etzerodt, Anders
AU - Mikkelsen, Jakob Hauge
AU - Torvund-Jensen, Morten
AU - Hennig, Dorle
AU - Boesen, Thomas
AU - Graversen, Jonas Heilskov
AU - Moestrup, Søren Kragh
AU - Kollman, Justin M
AU - Andersen, Christian Brix Folsted
N1 - © 2024. The Author(s).
PY - 2024/12/30
Y1 - 2024/12/30
N2 - 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.
AB - 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.
KW - Haptoglobins/metabolism
KW - Antigens, Differentiation, Myelomonocytic/metabolism
KW - Humans
KW - Antigens, CD/metabolism
KW - Cryoelectron Microscopy
KW - Receptors, Cell Surface/metabolism
KW - Hemoglobins/metabolism
KW - Calcium/metabolism
KW - Protein Binding
KW - Binding Sites
KW - Models, Molecular
KW - Protein Multimerization
UR - http://www.scopus.com/inward/record.url?scp=85213699715&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-55171-4
DO - 10.1038/s41467-024-55171-4
M3 - Journal article
C2 - 39738064
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 10871
ER -