Changing Ligand Specificities of αvβ1 and αvβ3 Integrins by Swapping a Short Diverse Sequence of the β Subunit (original) (raw)

Integrins mediate signal transduction through interaction with multiple cellular or extracellular matrix ligands. Integrin ␣v␤3 recognizes fibrinogen, von Willebrand factor, and vitronectin, while ␣v␤1 does not. We studied the mechanisms for defining ligand specificity of these integrins by swapping the highly diverse sequences in the I domain-like structure of the ␤1 and ␤3 subunits. When the sequence CTSEQNC (residues 187-193) of ␤1 is replaced with the corresponding CYD-MKTTC sequence of ␤3, the ligand specificity of ␣v␤1 is altered. The mutant (␣v␤1-3-1), like ␣v␤3, recognizes fibrinogen, von Willebrand factor, and vitronectin (a gain-of-function effect). The ␣v␤1-3-1 mutant is recruited to focal contacts on fibrinogen and vitronectin, suggesting that the mutant transduces intracellular signals on adhesion. The reciprocal ␤3-1-3 mutation blocks binding of ␣v␤3 to these multiple ligands and to LM609, a function-blocking anti-␣v␤3 antibody. These results suggest that the highly divergent sequence is a key determinant of integrin ligand specificity. Also, the data support a recent hypothetical model of the I domain of ␤, in which the sequence is located in the ligand binding site.