| ADAMs (a disintegrin and metalloprotease) are a family of novel proteins possessing functional adhesive and proteolytic domains. Due to the extensive homology with integrin antagonists contained in snake venom, the disintegrin domains of the ADAM family have been postulated to act as integrin ligands. By characterizing the integrin recognition properties of the human disintegrin-like domains of ADAM7, ADAM28, and ADAM33, the present study established that the disintegrin domains of multiple mammalian ADAMs are ligands for the α4/α9 functional subset of the integrin receptor family. Cell adhesion experiments demonstrated that the ADAM7 and ADAM28 recombinant disintegrin domains facilitated α4β1 and α4β7-dependent cell adhesion while the ADAM33 disintegrin domain did not. Integrin α4β1 and α4β7 recognition of ADAM7 and ADAM28 was shown to be activation-dependent requiring either the presence of Mn++ or an activating antibody for producing measurable cell attachment Alpha9-transfected Chinese hamster ovary cells significantly adhered to all three of the disintegrins studied. Further investigation demonstrated that multiple charged residues located outside of the disintegrin loop, a region previously implicated in adhesion to ADAMs, are essential for maintaining the α4β1 ligand properties of ADAM28. Mutagenesis results indicated that integrin recognition of a mammalian disintegrin by multiple receptors utilized a conserved integrin recognition interface while integrin binding surfaces between ADAMs were overlapping but distinct. |
