IDENTIFICATION OF A SEQUENCE THAT MEDIATES PROMISCUOUS BINDING OF INVARIANT CHAIN TO MHC CLASS-II ALLOTYPES

The invariant chain (Ii) shows promiscuous binding to a great variety of MHC class II allotypes, In contrast, the affinities of the Ii-deriv ed fragments, class II-associated Ii peptides, show large differences in binding to class II allotypes, The promiscuous association of Ii to all class II polypeptides therefore requires an additional contact si te to stabilize the interaction to the polymorphic class II cleft, We constructed recombinant molecules containing the class II binding site of Ii (CBS) and tested their association with HLA-DR dimers, The CBS fused to the transferrin receptor, mediates binding of transferrin rec eptor-CBS to class II dimers, Within the CBS, deletion of a sequence N -terminal to the groove-binding motif abolished binding of Ii to DR, A promiscuous class II binding site was identified by reinsertion of th e N-terminal residues, amino acids 81-87, of Ii into an Ii mutant that lacks the groove-binding segment, DR allotype-dependent association o f Ii was achieved by insertion of antigenic sequences, The promiscuous association, in contrast to the class II allotype-dependent binding o f Ii, is important to prevent interaction of class II dimers to nascen t polypeptides in the endoplasmic reticulum.