α3β1 Adhesion to laminin-5 and invasin: Critical and differential role of integrin residues clustered at the boundary between α3 N-terminal repeats 2 and 3

Integrin/ligand interaction is a therapeutic target for many diseases. We previously reported that residues critical for ligand binding are clustered in N-terminal repeat 3 (in the predicted 2-3 loop) of α4, α5 and αIIb. Here we have localized residues critical for ligand binding in the α3 subunit of integrin α3β1 with distinct ligand specificity (laminin-5). We identified an α3 epitope common to several function-blocking anti-α3 antibodies at the boundary between repeats 1 and 2 (residues 75−80). We found that swapping the predicted 4-1 loop (residues 153−165) at the boundary between repeats 2 and 3 with the corresponding α4 sequence and mutating Thr-162 and Gly-163 residues in this predicted loop block laminin-5 binding. Thr-162 and Gly-163 and the antibody epitope are separated in the primary structure; however, they are close to each other in the proposed β-propeller model. Mutating residues recently reported to block (Tyr-186 and Trp-188) or enhance (Asp-122) laminin-5 binding to α3β1 [Krukonis, E. S...