Structural Characteristics of RAGE and Its Ligand-Binding Sites

Receptor for Advanced Glycation Endproducts, RAGE, is a transmembrane multi-ligand receptor, which plays key role in amplifying immune response in numerous inflammatory processes and serious diseases. RAGE fulfills its function through binding of a variety of ligands. The structure of RAGE includes one transmembrane domain, one immunoglobulin V-like domain and two immunoglobulin C-like domains. Here, we have used combination of methods of domain structure analysis, fold classification, structure comparison and analysis of protein/ligand interactions with a chosen set of domains of RAGE and other immunoglobulin-like proteins from several different structural databases to describe structure-functional core and ligand recognition by the V-type domain of RAGE, and compare those to the other immunoglobulin-like proteins. We show that from one hand, similar to the other immunoglobulin-like proteins, RAGE contains a conserved substructure, the cross-β zone, with the cross-β motif at its core. The cross-β zone incorporates the hydrophobic core of RAGE and two multivalent surface ligand-binding sites for small molecules and proteins, one on the surface of the C-F-G β-sheet of the β-sheet sandwich, and the other formed by the CE-loop region. RAGE oligomerization allows RAGE to bind nucleic acids at a site different from the two mentioned above, leading to at least four distinct sites on the surface of RAGE: two for binding small molecules and proteins, one for binding nucleic acids, and one for RAGE dimerization. From the other hand, regardless of structural similarities with immunoglobulins, RAGE does not contain ligand-binding regions analogous to Complementary-Determining Regions in immunoglobulins, thus making RAGE and immunoglobulins functionally different.