Structure of the inflammatory homing receptor CD44 complexed with its pericellular matrix ligand hyaluronan.

Abstract

The hyaluronan receptor CD44 mediates cell adhesion/migration through tissue matrix during embryonic morphogenesis, tissue repair and leukocyte homing. However, despite their fundamental importance, the precise molecular details of CD44:hyaluronan interactions remain unknown. Here we have determined the crystal structure of the hyaluronan-binding domain complexed with a hyaluronan octasaccharide. This identifies the binding surface as a shallow groove in the main link module lined by a cluster of predominantly hydrophobic residues (tyrosine, alanine and isoleucine) and two key arginines, that together co-ordinate four sugars (GlcUA5-GlcNAc8) of the bound octasaccharide via hydrogen bonds rather than aromatic sugar stacking or ionic interactions. Moreover, we show that the complex experiences a conformational shift within the binding groove that brings an essential arginine residue (Arg45) into contact with ligand. A number of other residues within the link extension previously implicated in ligand-binding, make no apparent contacts with ligand. These data define a molecular interaction of fundamental importance to cell migration as well as providing the basis necessary for rational design of small molecule inhibitors for the treatment of inflammatory disease.