Adhesion to collagens by most cell types is mediated by the integrins a1b1 and a2b1. Both integrin a subunits belong to a group which is characterized by the presence of an I domain in the N-terminal half of the molecule, and this domain has been implicated in the ligand recognition. Since purified a1b1 and a2b1 differ in their binding to collagens I and IV and recognize different sites within the major cell binding domain of collagen IV, we investigated the potential role of the a1 and a2 I domains in specific collagen adhesion. We find that introducing the a2 I domain into a1 results in surface expression of a functional collagen receptor. The adhesion mediated by this chimeric receptor (a1-2-1b1) is similar to the adhesion profile conferred by a2b1, not a1b1. The presence of a2 or a1-2-1 results in preferential binding to collagen I, whereas a1 expressing cells bind better to collagen IV. In addition, a1 containing cells bind to low amounts of a tryptic fragment of collagen IV, whereas a2 or a1-2-1 bearing cells adhere only to high concentrations of this substrate. We also find that collagen adhesion of NIH-3T3 mediated by a2b1 or a1-2-1b1, but not by a1, requires the presence of Mn 2/ ions. This ion requirement was not found in CHO cells, implicating the I domain in cell type-specific activation of integrins.