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A novel domain on HLA-DRβ chain regulates the chaperone role of the invariant chain

The human lymphocyte antigen (HLA) class II region encodes highly polymorphic peptide receptors, which associate in the ER to the chaperone invariant chain (Ii). Ii facilitates assembly of class II subunits to functional peptide receptors. We searched for a conserved structure on HLA-DR polypeptides that mediates contact to a previously identified proline-rich class-II-binding sequence of Ii. Major histocompatibility complex (MHC) class II β chain sequences exhibit two conserved tryptophan residues separated by 22 amino acids. Inspection of this motif in the X-ray structure of DR3 showed TrpTyr residues in the vicinity of the Ii-derived fragment CLIP. Five DRβ mutants were produced. Mutation at Tyr123, Trp153 and Asp152 residues abolished interaction to the proline-rich sequence of Ii. All mutants formed heterodimers with DRα, were capable of binding an antigenic sequence and were expressed on the cell surface of transfected cells. In the presence of endogenous DRβ chain however, the TyrAspTrp mutant was not cell-surface exposed and did not co-isolate with Ii or DRα. The competition of the mutant with the endogenous DRβ for binding to DRα indicates that a structure on DRβ chain regulates assembly of DR subunits. Hence, the chaperone function of Ii is mediated through a conserved region on the β2 domain of class II.