CoChat
Sign Up
Cited by 7Hemoglobin structure and functionHeme Oxygenase-1 and Carbon MonoxidePhagocytosis and Immune Regulation

The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.

Scavenger receptor CD163 multimerises to allow uptake of diverse ligands

Open access
Zhou, Richard X., Higgins, Matthew K.·2025·Nature Communications
DOI 10.1038/s41467-025-62054-9PMC PMC12274614

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

Abstract

CD163 is an archetypal scavenger receptor and mediates detoxification of free haemoglobin. Release of haemoglobin from lysed erythrocytes causes oxidative tissue and organ damage. Detoxification involves haemoglobin binding to the abundant serum protein haptoglobin, followed by CD163-mediated uptake of stoichiometrically diverse haptoglobin-haemoglobin complexes into macrophages for degradation. We show that CD163 adopts dimeric and trimeric assemblies due to calcium-mediated interactions within a membrane-associated base. Arms protrude from this base and create a ligand-binding site. Flexibility within the base, coupled with multiple small ligand-binding surfaces on each arm, allow the receptor to mould around its ligands, resulting in promiscuous uptake of ligands with different structures and stoichiometries. Monomeric CD163 lacks this ability to internalise lower-avidity ligands. Arms from adjacent protomers can also self-associate, blocking ligand-binding surfaces in an autoinhibited state. Therefore, through calcium-dependent multimer formation and flexible ligand binding, CD163 scavenges ligands with different structures and avidities, mediating haemoglobin detoxification.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-025-62054-9

Cites

3 of 3 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 32

  1. Kumar, S. & Bandyopadhyay, U. Free heme toxicity and its detoxification systems in human. Toxicol. Lett. 157, 175–188 (2005). · DOI · Paper page
  2. Sadrzadeh, S. M., Graf, E., Panter, S. S., Hallaway, P. E. & Eaton, J. W. Hemoglobin. A biologic fenton reagent. J. Biol. Chem. 259, 14354–14356 (1984). · DOI
  3. Gutteridge, J. M. Lipid peroxidation and antioxidants as biomarkers of tissue damage. Clin. Chem. 41, 1819–1828 (1995). · DOI
  4. Pamplona, A., Hanscheid, T., Epiphanio, S., Mota, M. M. & Vigario, A. M. Cerebral malaria and the hemolysis/methemoglobin/heme hypothesis: shedding new light on an old disease. Int. J. Biochem. Cell Biol. 41, 711–716 (2009). · DOI
  5. Andersen, C. B. et al. Structure of the haptoglobin-haemoglobin complex. Nature 489, 456–459 (2012). · DOI
  6. Wejman, J. C., Hovsepian, D., Wall, J. S., Hainfeld, J. F. & Greer, J. Structure of haptoglobin and the haptoglobin-hemoglobin complex by electron microscopy. J. Mol. Biol. 174, 319–341 (1984). · DOI
  7. Maeda, N., Yang, F., Barnett, D. R., Bowman, B. H. & Smithies, O. Duplication within the haptoglobin Hp2 gene. Nature 309, 131–135 (1984). · DOI
  8. Smithies, O. Zone electrophoresis in starch gels: group variations in the serum proteins of normal human adults. Biochem. J. 61, 629–641 (1955). · DOI
  9. Andersen, C. B. F. et al. Haptoglobin. Antioxid. Redox Signal 26, 814–831 (2017). · DOI
  10. Tamara, S., Franc, V. & Heck, A. J. R. A wealth of genotype-specific proteoforms fine-tunes hemoglobin scavenging by haptoglobin. Proc. Natl Acad. Sci. USA 117, 15554–15564 (2020). · DOI
  11. Kristiansen, M. et al. Identification of the haemoglobin scavenger receptor. Nature 409, 198–201 (2001). · DOI · Paper page
  12. Law, S. K. et al. A new macrophage differentiation antigen which is a member of the scavenger receptor superfamily. Eur. J. Immunol. 23, 2320–2325 (1993). · DOI
  13. Madsen, M. et al. Molecular characterization of the haptoglobin.hemoglobin receptor CD163. Ligand binding properties of the scavenger receptor cysteine-rich domain region. J. Biol. Chem. 279, 51561–51567 (2004). · DOI
  14. Nielsen, M. J., Andersen, C. B. & Moestrup, S. K. CD163 binding to haptoglobin-hemoglobin complexes involves a dual-point electrostatic receptor-ligand pairing. J. Biol. Chem. 288, 18834–18841 (2013). · DOI
  15. Ojala, J. R., Pikkarainen, T., Tuuttila, A., Sandalova, T. & Tryggvason, K. Crystal structure of the cysteine-rich domain of scavenger receptor MARCO reveals the presence of a basic and an acidic cluster that both contribute to ligand recognition. J. Biol. Chem. 282, 16654–16666 (2007). · DOI
  16. Schaer, D. J. et al. CD163 is the macrophage scavenger receptor for native and chemically modified hemoglobins in the absence of haptoglobin. Blood 107, 373–380 (2006). · DOI · Paper page
  17. Lane-Serff, H., MacGregor, P., Lowe, E. D., Carrington, M. & Higgins, M. K. Structural basis for ligand and innate immunity factor uptake by the trypanosome haptoglobin-haemoglobin receptor. Elife 3, e05553 (2014). · DOI
  18. Caesar, J. et al. SIMPLE 3.0. Stream single-particle cryo-EM analysis in real time. J. Struct. Biol. X 4, 100040 (2020).
  19. Punjani, A., Rubinstein, J. L., Fleet, D. J. & Brubaker, M. A. cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination. Nat. Methods 14, 290–296 (2017). · DOI · Paper page
  20. Drain, J., Bishop, J. R. & Hajduk, S. L. Haptoglobin-related protein mediates trypanosome lytic factor binding to trypanosomes. J. Biol. Chem. 276, 30254–30260 (2001). · DOI
  21. Nielsen, M. J. et al. Haptoglobin-related protein is a high-affinity hemoglobin-binding plasma protein. Blood 108, 2846–2849 (2006). · DOI
  22. Vanhollebeke, B. et al. A haptoglobin-hemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans. Science 320, 677–681 (2008). · DOI
  23. Langlois, M. R. & Delanghe, J. R. Biological and clinical significance of haptoglobin polymorphism in humans. Clin. Chem. 42, 1589–1600 (1996). · DOI
  24. Nagel, R. L. & Gibson, Q. H. The binding of hemoglobin to haptoglobin and its relation to subunit dissociation of hemoglobin. J. Biol. Chem. 246, 69–73 (1971). · DOI
  25. Etzerodt, A. et al. The Cryo-EM structure of human CD163 bound to haptoglobin-hemoglobin reveals molecular mechanisms of hemoglobin scavenging. Nat. Commun. 15, 10871 (2024). · DOI
  26. Aricescu, A. R., Lu, W. & Jones, E. Y. A time- and cost-efficient system for high-level protein production in mammalian cells. Acta Crystallogr. D. Biol. Crystallogr. 62, 1243–1250 (2006). · DOI
  27. Sanchez-Garcia, R. et al. DeepEMhancer: a deep learning solution for cryo-EM volume post-processing. Commun. Biol. 4, 874 (2021). · DOI
  28. Meng, E. C. et al. UCSF ChimeraX: tools for structure building and analysis. Protein Sci. 32, e4792 (2023). · DOI
  29. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D. Biol. Crystallogr. 66, 486–501 (2010). · DOI · Paper page
  30. Croll, T. I. ISOLDE: a physically realistic environment for model building into low-resolution electron-density maps. Acta Crystallogr. D. Struct. Biol. 74, 519–530 (2018). · DOI
  31. Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D. Struct. Biol. 75, 861–877 (2019). · DOI · Paper page
  32. Krissinel, E. & Henrick, K. Inference of macromolecular assemblies from crystalline state. J. Mol. Biol. 372, 774–797 (2007). · DOI

Metadata

Authors
Zhou, R. X., & Higgins, M. K.
Affiliations
University of Oxford (GB)
Corresponding author
Higgins, Matthew K.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2025-07-18
Volume
16
Issue
1
Pages
6623-6623
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-025-62054-9
PMC
PMC12274614
OpenAlex
W4412522853
Cited by
7
References
3
Citations by year
2026: 6 · 2025: 1
FWCI
3.50
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Wellcome Trust (220797/Z/20/Z, 218482/Z/19/Z)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Hemoglobin structure and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heme Oxygenase-1 and Carbon Monoxide
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
CD163, scavenger receptors, receptor multimerization, macrophages, autoinhibition, hemolysis
MeSH terms
CD163 Antigen, Animals, Binding Sites, Calcium, Haptoglobins, Hemoglobins, Humans, Ligands, Macrophages, Protein Binding, Receptors, Cell Surface, Antigens, Differentiation, Myelomonocytic, Antigens, CD, Receptors, Scavenger, Mice, Protein Multimerization

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review