Molecular characterization of the haptoglobin.hemoglobin receptor CD163: Ligand binding properties of the scavenger receptor cysteine-rich domain region

Mette Madsen, Holger J Møller, Marianne Jensby Nielsen, Christian Jacobsen, Jonas Heilskov Graversen, Timo van den Berg, Søren K Moestrup*

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Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Abstrakt

CD163 is the macrophage receptor for endocytosis of haptoglobin.hemoglobin complexes. The extracellular region consisting of nine scavenger receptor cysteine rich (SRCR) domains also circulates in plasma as a soluble protein. By ligand binding analysis of a broad spectrum of soluble CD163 truncation variants, the amino-terminal third of the SRCR region was shown to be crucial for the binding of haptoglobin.hemoglobin complexes. By Western blotting of the CD163 variants, a panel of ten monoclonal antibodies was mapped to SRCR domains 1, 3, 4, 6, 7, and 9, respectively. Only the two antibodies binding to SRCR domain 3 exhibited effective inhibition of ligand binding. Furthermore, analysis of purified native CD163 revealed that proteolytic cleavage in SRCR domain 3 inactivates ligand binding. Calcium protects against cleavage in this domain. Analysis of the calcium sensitivity of ligand binding to CD163 demonstrated that optimal ligand binding requires physiological plasma calcium concentrations, and an immediate ligand release occurs at the low calcium concentrations measured in acidifying endosomes. In conclusion, SRCR domain 3 of CD163 is an exposed domain and a critical determinant for the calcium-sensitive coupling of haptoglobin.hemoglobin complexes.

OriginalsprogEngelsk
TidsskriftJournal of Biological Chemistry
Vol/bind279
Udgave nummer49
Sider (fra-til)51561-51567
ISSN0021-9258
DOI
StatusUdgivet - 3. dec. 2004
Udgivet eksterntJa

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