Disassociation of CLIP from MHC II

Stable Identifier
Reaction [transition]
Homo sapiens
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To gain the capacity to activate antigen-specific T cells, MHC class II-associated CLIP must be exchanged for an antigenic peptide (Kropshofer et al. 1999). There are two CLIP variants in humans: CLIP(long) with 21-26 residues, and CLIP(short) with 14-19 residues. CLIP(long) disassociates rapidly from HLA-DR molecules at endosomal/lysosomal pH, whereas CLIP(short) displays a lower off-rate. The N-terminal 9 residues of CLIP (81-89) facilitate its rapid release (Urban et al. 1994, Kropshofer et al. 1995a, Kropshofer et al. 1995b). The non-classical MHC class II molecule HLA-DM (DM) functions as a mediator of peptide exchange by accelerating the removal of CLIP. DM mediated peptide release involves a direct interaction between DM and the class II molecule. In addition to peptide release, DM also acts as a chaperone for MHC class II molecules in endosomal/lysosomal compartments. It stabilizes the peptide-receptive empty MHC II molecules and prevents them from unfolding and also favors the generation of high-stability peptide-MHC class II complexes by promoting release of low-stability peptide ligands (Kropshofer et al. 1999, Kropshofer et al. 1997). Another non-classical MHC II molecule HLA-DO (DO), only expressed in B-cells and thymic epithelial cells, binds tightly to DM modulating DM activity both negatively and positively, depending on the amount of DO present in an APC. Heterotypic DR-DM-DO complexes are receptive for peptide loading, in these complexes DO does not appear to be inhibitory (Denzin et al. 1997, Kropshofer et al. 1998, Kropshofer et al. 1999).
Literature References
PubMed ID Title Journal Year
9311912 Negative regulation by HLA-DO of MHC class II-restricted antigen processing

Hammond, C, Sant'Angelo, DB, Surman, MJ, Cresswell, P, Denzin, LK

Science 1997
8046351 Selective release of some invariant chain-derived peptides from HLA-DR1 molecules at endosomal pH

Chicz, RM, Urban, RG, Strominger, JL

J Exp Med 1994
9606180 A role for HLA-DO as a co-chaperone of HLA-DM in peptide loading of MHC class II molecules

Moldenhauer, G, Armandola, EA, Thery, C, Kropshofer, H, Li, BC, Vogt, AB, Amigorena, S, Hämmerling, GJ

EMBO J 1998
7667286 Structural features of the invariant chain fragment CLIP controlling rapid release from HLA-DR molecules and inhibition of peptide binding

Kropshofer, H, Vogt, AB, Hämmerling, GJ

Proc Natl Acad Sci U S A 1995
7481823 Self-release of CLIP in peptide loading of HLA-DR molecules

Kropshofer, H, Vogt, AB, Stern, LJ, Hämmerling, GJ

Science 1995
10631952 The impact of the non-classical MHC proteins HLA-DM and HLA-DO on loading of MHC class II molecules

Kropshofer, H, Vogt, AB, Hämmerling, GJ

Immunol Rev 1999
9075930 HLA-DM acts as a molecular chaperone and rescues empty HLA-DR molecules at lysosomal pH

Moldenhauer, G, Kropshofer, H, Arndt, SO, Vogt, AB, Hämmerling, GJ

Immunity 1997
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