CD163 binding

Even though the series protease domain has general structural similarity to chymotrypsin-like proteases, the size and conformation of some loops on the surface of the serine protease domain of Hp are different. Especially the loop 3 in Hp has a difference in length and protrusion and allows recognition of the complex by the CD163 scavenger receptor of macrophages as shown in small angle X-ray scattering experiments (Andersen et al., 2012). The main residues that are involved in that binding are residues V259, E261, K262, and T264 on the tip of the loop (Figure 9). They interact with domain three of CD163. Binding of CD163 leads to endocytosis of the Hp-Hb complex and degradation of the haem groups in the macrophage by haem-oxygenase enzymes (Fabriek, Dijkstra and van den Berg, 2005).

Figure 9: Loop 3 region of haptoglobin with residues involved in CD163 binding labelled.

Binding Orientation Models of the Hp-Hb complex to CD163 

It is not known in which orientation the CD163 receptor domains bind the Hp-Hb-complex. Two models show possible binding of the domains 1-5 of CD163 (Figure 10). After receptor binding the Hp-Hb-complex is endocytosed by the macrophage and the tissue is protected from the reactive haem groups (Andersen et al., 2012).

Figure 10: Models a) and b) for the binding orientation of CD163 scavenger receptor (taken from Andersen et al., 2012). Molecules are shown as spheres with haemoglobin (orange), haptoglobin (blue), CD163 domains (green) and the macrophage plasma membrane (grey).