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TitleScavenger receptor CD163 multimerises to allow uptake of diverse ligands.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 6623, Year 2025
Publish dateJul 18, 2025
AuthorsRichard X Zhou / Matthew K Higgins /
PubMed AbstractCD163 is an archetypal scavenger receptor and mediates detoxification of free haemoglobin. Release of haemoglobin from lysed erythrocytes causes oxidative tissue and organ damage. Detoxification ...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.
External linksNat Commun / PubMed:40681524 / PubMed Central
MethodsEM (single particle)
Resolution2.82 - 3.81 Å
Structure data

EMDB-52078, PDB-9hej:
Dimeric CD163 bound to human haptoglobin-haemoglobin complex
Method: EM (single particle) / Resolution: 2.82 Å

EMDB-52079, PDB-9hek:
Trimeric CD163 bound to human haptoglobin-haemoglobin complex
Method: EM (single particle) / Resolution: 3.15 Å

EMDB-52080, PDB-9hel:
Unliganded dimeric CD163 with arm-arm contacts
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-52081: Unliganded trimeric CD163 with arm-arm interactions
Method: EM (single particle) / Resolution: 3.37 Å

EMDB-52082: Unliganded trimeric CD163 with disordered arms
Method: EM (single particle) / Resolution: 3.81 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-CA:
Unknown entry

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

ChemComp-OXY:
OXYGEN MOLECULE

Source
  • homo sapiens (human)
KeywordsENDOCYTOSIS / CD163 / haptoglobin-haemoglobin complex / haemoglobin detoxification / ligand uptake / scavenger receptor / SRCR domain-containing protein

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