CHANGING LIGAND SPECIFICITIES OF ALPHA-V-BETA-1 AND ALPHA-V-BETA-3 INTEGRINS BY SWAPPING A SHORT DIVERSE SEQUENCE OF THE BETA-SUBUNIT

Integrins mediate signal transduction through interaction with multipl e cellular or extracellular matrix ligands. Integrin alpha v beta 3 re cognizes fibrinogen, von Willebrand factor, and vitronectin, while alp ha v beta 1 does not. We studied the mechanisms for defining ligand sp ecificity of these integrins by swapping the highly diverse sequences in the I domain-like structure of the beta 1 and beta 3 subunits. When the sequence CTSEQNC (residues 187-193) of beta 1 is replaced with th e corresponding CYD-MKTTC sequence of beta 3, the ligand specificity o f alpha v beta 1 is altered. The mutant (alpha v beta 1-3-1), like alp ha v beta 3, recognizes fibrinogen, von Willebrand factor, and vitrone ctin (a gain-of-function effect). The alpha v beta 1-3-1 mutant is rec ruited to focal contacts on fibrinogen and vitronectin, suggesting tha t the mutant transduces intracellular signals on adhesion. The recipro cal beta 3-1-3 mutation blocks binding of alpha v beta 3 to these mult iple ligands and to LM609, a function-blocking anti-alpha v beta 3 ant ibody. These results suggest that the highly divergent sequence is a k ey determinant of integrin ligand specificity. Also, the data support a recent hypothetical model of the I domain of beta, in which the sequ ence is located in the ligand binding site.