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TitleStructural elucidation of the haptoglobin-hemoglobin clearance mechanism by macrophage scavenger receptor CD163.
Journal, issue, pagesPLoS Biol, Vol. 23, Issue 7, Page e3003264, Year 2025
Publish dateJul 11, 2025
AuthorsChing-Shin Huang / Hui Wang / Joshua B R White / Oksana Degtjarik / Cindy Huynh / Kristoffer Brannstrom / Mark T Horn / Stephen P Muench / William S Somers / Javier Chaparro-Riggers / Laura Lin / Lidia Mosyak /
PubMed AbstractIntravascular hemolysis releases hemoglobin into the bloodstream, which can damage vascular and renal tissues due to its oxidative nature. Circulating haptoglobin acts as a primary defense by binding ...Intravascular hemolysis releases hemoglobin into the bloodstream, which can damage vascular and renal tissues due to its oxidative nature. Circulating haptoglobin acts as a primary defense by binding to free hemoglobin, forming a haptoglobin-hemoglobin (HpHb) complex that is then recognized and cleared by the CD163 scavenger receptor on macrophages. While the function and structure of HpHb complex are mostly well-defined, the molecular mechanism underlying its interaction with CD163 remains unclear. Here we report the cryo-electron microscopy structures of human CD163 in its unliganded state and in its complex with HpHb. These structures reveal that CD163 functions as a trimer, forming a composite binding site at its center for one protomer of the dimeric HpHb, resulting in a 3:1 binding stoichiometry. In the unliganded state, CD163 can also form a trimer, but in an autoinhibitory configuration that occludes the ligand binding site. Widespread electrostatic interactions mediated by calcium ions are pivotal in both pre-ligand and ligand-bound receptor assemblies. This calcium-dependent mechanism enables CD163/HpHb complexes to assemble and, once internalized, disassemble into individual components upon reaching the endosome, where low calcium and lower pH conditions prevail. Collectively, this study elucidates the molecular mechanism by which CD163-mediated endocytosis efficiently clears different isoforms of HpHb.
External linksPLoS Biol / PubMed:40644526 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 4.1 Å
Structure data

EMDB-49208: Consensus map of the autoinhibitory unliganded CD163 trimer (map A)
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-49209: Local map of the autoinhibitory unliganded CD163 trimer (map B)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-49210: Local map of the autoinhibitory unliganded CD163 trimer (map C)
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-49211: Local map of the autoinhibitory unliganded CD163 trimer (map D)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-49212: Local map of the autoinhibitory unliganded CD163 trimer (map E)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-49213: Composite map of the autoinhibitory unliganded CD163 trimer (map F)
PDB-9nb5: Cryo-EM structure of the autoinhibitory CD163 trimer
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-49214: Consensus map of the CD163/Hp(1-1)Hb complex (Map G)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-49215: Local map of the CD163/Hp(1-1)Hb complex (Map H)
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-49216: Local map of the CD163/Hp(1-1)Hb complex (Map I)
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-49217: Local map of the CD163/Hp(1-1)Hb complex (Map J)
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-49218: Composite map of the CD163/Hp(1-1)Hb complex (Map K)
PDB-9nb6: Cryo-EM structure of the CD163/Hp(1-1)Hb complex
Method: EM (single particle) / Resolution: 3.3 Å

EMDB-49219: Consensus map of the CD163/HpSPHb complex (Map L)
Method: EM (single particle) / Resolution: 4.0 Å

EMDB-49220: Local map of the CD163/HpSPHb complex (Map M)
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-49221: Composite map of the CD163/HpSPHb complex (Map M)
PDB-9nb8: Cryo-EM structure of the CD163/HpSPHb complex
Method: EM (single particle) / Resolution: 4.0 Å

Chemicals

ChemComp-CA:
Unknown entry

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

ChemComp-HEM:
PROTOPORPHYRIN IX CONTAINING FE

ChemComp-OXY:
OXYGEN MOLECULE

Source
  • homo sapiens (human)
KeywordsENDOCYTOSIS / CD163 / M130 / Scavenger receptor / Haptoglobin / Hemoglobin / Hb / Hp / HpHb / Hp(1-1)Hb / hemolysis

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