The primary structure of the α⁴ subunit of VLA-4: Homology to other integrins and a possible cell-cell adhesion function

VLA-4 is a cell surface heterodimer in the integrin superfamily of adhesion receptors. Anti-VLA-4 antibodies inhibited cytolytic T cell activity, with inhibitory activity directed against the effector T cells rather than their targets. Thus, whereas other VLA receptors appear to mediate cell-matrix interactions, VLA-4 may have a cell-cell adhesion function. To facilitate comparative studies of VLA-4 and other integrins, cDNA clones for the human α⁴ subunit of VLA-4 were selected and then sequenced. The 3805 bp sequence encoded for 999 amino acids, with an N-terminus identical to that previously obtained from direct sequencing of purified α⁴ protein. The α⁴ amino acid sequence was 17-24% similar to other integrin α chains with known sequences. Part of the α⁴ sequence most conserved in other α chains include (i) the positions of 19/24 cysteine residues, (ii) three potential divalent cation binding sites of the general structure DXDXDGXXD and (iii) the transmembrane region. However, α⁴ stands apart from all other known integrin α subunit sequences because (i) α⁴ has neither an inserted I-domain, nor a disulfide-linked C-terminal fragment, (ii) its sequence is the most unique and (iii) only α⁴ has a potential protease cleavage site, near the middle of the coding region, which appears responsible for the characteristic 80000 and 70000 M(r) fragments of α⁴.