Structural and mutational analyses of a CD8αβ heterodimer and comparison with the CD8αα homodimer

The crystal structure of a recombinant mouse single chain CD8 alpha beta ectodomains at 2.4 A resolution reveals paired immunoglobulin variable region-like domains with a striking resemblance to CD8 alpha alpha in size, shape, and surface electrostatic potential of complementarity determining regions (CDR), despite < 20% sequence identity between the CD8 alpha and CD8 beta subunits. Unlike the CD8 alpha subunit(s) in the heterodimer or homodimer, the CDR1 loop of CD8 beta tilts away from its corresponding CDR2 and CDR3 loops. Consistent with this observation, independent mutational studies reveal that alanine substitutions of residues in the CDR1 loop of CD8 beta have no effect on CD8 alpha beta coreceptor function, whereas mutations in CD8 beta CDR2 and CDR3 loops abolish CD8 alpha beta coreceptor activity. The implications of these findings and additional CD8 alpha beta mutational studies for CD8 alpha beta- versus CD8 alpha-MHCI binding are discussed.