AMINO-ACID-RESIDUES ESSENTIAL FOR BIOLOGICAL-ACTIVITY OF A PEPTIDE DERIVED FROM A MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I ANTIGEN

The stimulatory activity of peptides from the al domain of the major h istocompatibility complex (MHC) class I antigen on adipose cell glucos e transport was previously shown to require a preformed, ordered confo rmation of the peptide. The two peptides studied previously were D(k)- (61-85) (ERETQIAKGNEQSFRVDLRTLLRYY) and D(k)-(69-85). We now show that systematic alanine substitution in D(k)-(69-85) identifies residues t hat are essential for biological activity. Ordered structure of the pe ptides, estimated by circular dichroism, was found in all peptides wit h activity, but with a complex variety of spectra. Inactive peptides w ere in either a random coil or an ordered structure. Ordered structure , therefore, is not sufficient for activity. The peptides self-interac t in the absence of cells and form aggregates that precipitate upon ce ntrifugation. The tendency to aggregate is correlated with biological potency. Only MHC class I molecules have significant homology to the p eptides studied here. The peptide self-interaction suggests that the b iological effects in cells, which result from inhibition of receptor a nd transporter internalization, may be due to the binding (tantamount to self-interaction) of the peptide to the homologous sequences in the alpha1 domain of the MHC class I molecule.