Structural specializations of \(\alpha_4 \beta_7\), an integrin that mediates rolling adhesion

Abstract

The lymphocyte homing receptor integrin \(\alpha_4 \beta_7\) is unusual for its ability to mediate both rolling and firm adhesion. \(\alpha_4 \beta_1\) and \(\alpha_4 \beta_7\) are targeted by therapeutics approved for multiple sclerosis and Crohn’s disease. Here, we show by electron microscopy and crystallography how two therapeutic Fabs, a small molecule (RO0505376), and mucosal adhesion molecule-1 (MAdCAM-1) bind α4β7. A long binding groove at the \(\alpha_4 -\beta_7\)interface for immunoglobulin superfamily domains differs in shape from integrin pockets that bind Arg-Gly-Asp motifs. RO0505376 mimics an Ile/Leu-Asp motif in \(\alpha_4\) ligands, and orients differently from Arg-Gly-Asp mimics. A novel auxiliary residue at the metal ion–dependent adhesion site in \(\alpha_4 \beta_7\) is essential for binding to MAdCAM-1 in \(Mg^{2+}\) yet swings away when RO0505376 binds. A novel intermediate conformation of the \(\alpha_4 \beta_7\) headpiece binds MAdCAM-1 and supports rolling adhesion. Lack of induction of the open headpiece conformation by ligand binding enables rolling adhesion to persist until integrin activation is signaled.