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Conformational alterations during biosynthesis of HLA-DR3 molecules controlled by invariant chain and HLA-DM
Journal article   Peer reviewed

Conformational alterations during biosynthesis of HLA-DR3 molecules controlled by invariant chain and HLA-DM

F A Verreck, C A Fargeas, G J Hämmerling and Irwin M Chaiken
European journal of immunology, v 31(4), pp 1029-1036
Apr 2001
DOI: https://doi.org/10.1002/1521-4141(200104)31:43.0.CO;2-Q
PMID: 11298327
Featured in Collection :   UN Sustainable Development Goals @ Drexel

Abstract

Amino Acid Sequence Amino Acid Substitution - genetics Antibodies, Monoclonal - immunology Antigens, Differentiation, B-Lymphocyte - chemistry Antigens, Differentiation, B-Lymphocyte - genetics Antigens, Differentiation, B-Lymphocyte - metabolism Cells, Cultured Detergents - metabolism Dimerization Endoplasmic Reticulum - metabolism Epitopes, T-Lymphocyte - immunology Flow Cytometry Gene Deletion HeLa Cells Histocompatibility Antigens Class II - chemistry Histocompatibility Antigens Class II - genetics Histocompatibility Antigens Class II - metabolism HLA-D Antigens - genetics HLA-D Antigens - metabolism HLA-DR3 Antigen - chemistry HLA-DR3 Antigen - genetics HLA-DR3 Antigen - immunology HLA-DR3 Antigen - metabolism Humans Lymphocyte Activation Lysine - genetics Lysine - metabolism Macromolecular Substances Molecular Sequence Data Peptides - chemistry Peptides - immunology Peptides - metabolism Precipitin Tests Protein Binding Protein Conformation T-Lymphocytes - immunology
HLA-DM is known to catalyze the exchange of class II-associated invariant chain (Ii) peptide (CLIP) for cognate peptide during biosynthesis. In DM-negative cells HLA-DR3 molecules have been shown to predominantly present CLIP and to lack the DR3-specific mAb epitope 16.23, which has led to the assumption that CLIP prevents binding of mAb 16.23. In the present study we show that CLIP does not prohibit 16.23 epitope expression, but that the formation of this epitope is directly influenced by interactions of the DR molecule with Ii and DM. Detergent solubilized DR3 from wild-type as well as DM(-) cells bound CLIP in a 16.23(+) mode. On cells, however, neither CLIP nor antigenic peptide bound to DR3 in a 16.23(+) conformation, unless HLA-DM was expressed. Thus, HLA-DM appears to alter the conformation of DR3 in a peptide-independent fashion. Since in DM-deficient cells that also lack Ii, DR3 molecules assembled in a 16.23(+) conformation, we conclude that during biosynthesis Ii and DM exert opposing conformational constraints, characterized by suppressing or releasing 16.23 epitope expression. These results imply that DR3/peptide complexes, including DR3/ CLIP, can exist in two conformations depending on previous interaction with DM, but independent of the nature of the peptide bound. We show that these naturally occurring class II conformers can be selectively recognized by T cells.

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Web of Science research areas
Immunology
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