Structural requirements of KTS-disintegrins for inhibition of α1β1 integrin
Résumé
Obtustatin and viperistatin represent the shortest known snake venom monomeric disintegrins. We have produced recombinant full-length wild-type and site-directed mutants of obtustatin to assess the role of the 21KTS23 tripeptide and C-terminal residues for specific inhibition of the a1b1 integrin. Threonine-22 appeared to be the most critical residue for disintegrin activity, whereas substitution of flanking lysine or serine for alanine resulted in less pronounced decreased of the disintegrin's anti-α1β1 integrin activity. The triple mutant 21AAA23 was devoid of blocking activity towards α1β1 integrin-mediated cell adhesion. The potency of recombinant KTS-disintegrins also depended on the residue C-terminally adjacent to the active motif. Substitution of wild-type obtustatin's leucine-24 for alanine slightly decreased the inhibitory activity of the mutant, whereas arginine in this position enhanced by 6-fold the potency of the mutant over wild type obtustatin. In addition, the replacements leucine-38/valine and proline-40/glutamine may account for a further 25-fold increase in α1β1 inhibitory potency of viperistatin over KTSR-obtustatin.
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