title: Structural features of the invariant chain fragment CLIP controlling rapid release from HLA-DR molecules and inhibition of peptide binding.
abstract: The invariant chain (Ii) prevents binding of ligands to major histocompatibility complex (MHC) class II molecules in the endoplasmic reticulum and during intracellular transport. Stepwise removal of the Ii in a trans-Golgi compartment renders MHC class II molecules accessible for peptide loading, with CLIP (class II-associated Ii peptides) as the final fragment to be released. Here we show that CLIP can be subdivided into distinct functional regions. The C-terminal segment (residues 92-105) of the CLIP-(81-105) fragment mediates inhibition of self- and antigenic peptide binding to HLA-DR2 molecules. In contrast, the N-terminal segment CLIP-(81-98) binds to the Staphylococcus aureus enterotoxin B contact site outside the peptide-binding groove on the alpha 1 domain and does not interfere with peptide binding. Its functional significance appears to lie in the contribution to CLIP removal: the dissociation of CLIP-(81-105) is characterized by a fast off-rate, which is accelerated at endosomal pH, whereas in the absence of the N-terminal CLIP-(81-91), the off-rate of C-terminal CLIP-(92-105) is slow and remains unaltered at low pH. Mechanistically, the N-terminal segment of CLIP seems to prevent tight interactions of CLIP side chains with specificity pockets in the peptide-binding groove that normally occurs during maturation of long-lived class II-peptide complexes.
authors.affiliation: Tumor Immunology Program, German Cancer Research Center, Heidelberg.
authors.forename: H
authors.initials: H
authors.lastname: Kropshofer
authors.forename: A B
authors.initials: AB
authors.lastname: Vogt
authors.forename: G J
authors.initials: GJ
authors.lastname: Hämmerling
mesh_terms: D000595:Amino Acid Sequence; D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry / Q000378:metabolism*; D002461:Cell Line, Transformed; D004768:Enterotoxins / Q000378:metabolism; D006684:HLA-DR Antigens / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D013211:Staphylococcus aureus / Q000378:metabolism
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D004768:Enterotoxins; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; C045084:invariant chain; C031818:enterotoxin B, staphylococcal