STRUCTURAL FEATURES OF THE INVARIANT CHAIN FRAGMENT CLIP CONTROLLING RAPID RELEASE FROM HLA-DR MOLECULES AND INHIBITION OF PEPTIDE BINDING

被引:51
作者
KROPSHOFER, H [1 ]
VOGT, AB [1 ]
HAMMERLING, GJ [1 ]
机构
[1] GERMAN CANC RES CTR,DIV MOLEC IMMUNOL,TUMOR IMMUNOL PROGRAM,D-69120 HEIDELBERG,GERMANY
关键词
HLA ANTIGENS; ANTIGEN PRESENTATION; KINETICS;
D O I
10.1073/pnas.92.18.8313
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:8313 / 8317
页数:5
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