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*
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322; and
Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 39912
The class II-associated invariant chain peptide (CLIP) region of
invariant chain (Ii) is believed to play a critical role in the
assembly and transport of MHC class II 
ßIi complexes through its
interaction with the class II peptide-binding site. The role of the
CLIP sequence was investigated by using mutant Ii molecules with
altered affinity for the DR1 peptide-binding site. Both high- and
low-affinity mutants were observed to efficiently assemble with DR1 and
mediate transport to endosomal compartments in COS cell transfectants.
Using N- and C-terminal truncations, a region adjacent to CLIP within
Ii(103–118) was identified that can complement loss of affinity for
the peptide-binding site in mediating efficient assembly of ßIi. A
C-terminal fragment completely lacking the CLIP region, Ii(103–216),
was observed binding stably to class II molecules in
immunoprecipitation studies and experiments with purified proteins. The
Ii(103–118) region was required for this binding, which occurs through
interactions outside of the ß peptide-binding groove. We conclude
that strong interactions involving Ii(103–118) and other regions of Ii
cooperate in the assembly of functional ßIi under conditions where
CLIP has little or no affinity for the class II peptide-binding site.
Our results support the hypothesis that the CLIP sequence has evolved
to avoid high-stability interactions with the peptide-binding sites of
MHC class II molecules rather than as a promiscuous binder with
moderate affinity for all class II molecules.
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