COEVOLUTION OF THE VERTEBRATE INTEGRIN ALPHA-CHAIN AND BETA-CHAIN GENES

The integrin receptors are heterodimers whose alpha and beta-subunits are encoded by separate, evolutionarily unrelated multigene families. Phylogenetic analysis of DNA sequences from these two gene families showed that they have not always evolved in a parallel fashion. The integrin alpha-chains that can form heterodimers with beta-1 do not constitute a monophyletic group, nor do the beta-chains which can form heterodimers with alpha-V. On the other hand, the vertebrate alpha-chains associating with beta-2 are a monophyletic group. In the metal cation-binding region of the alpha-chain, an exon exchange took place between human alpha-M and alpha-X approximately 40-50 Mya, homogenizing this functionally important region in these two alpha-chains. When integrin beta-chains of different functional classes are compared, nonsynonymous (amino acid altering) nucleotide substitutions that alter amino acid residue charge in the central region of the molecule occur at a rate significantly higher than that expected under random replacement. By contrast, when closely related beta-1 chains are compared, residue charge is conserved in this region. These results pinpoint the central region as a focus of functional divergence among integrin beta-chains, perhaps relating to the ability of each beta-integrin class to associate with a specific array of alpha-integrins. Furthermore, they imply that positive, directional selection on this region has occurred in the evolution of the integrin beta-chain gene family.