S M Weenink | PubMed Health

PubMed1997

Antigen presentation by MHC class II molecules.

The treamendous explosion in the field of MHC research in the last 5 years has significantly advanced our understanding of antigen processing pathways, particularly with regard to details of MHC class II-mediated antigen presentation. MHC class II molecules at the surface of antigen presenting cells present antigenic peptides to CD4+ T helper cells. However for effective cell surface antigen presentation, a number of highly synchronized events must first take place intracellulary. The monomorphic protein, invariant chain (Ii), is a crucial participant in MHC class II antigen presentation. Acting as a molecular chaperone, this molecule escorts the newly synthesized class II heterodimers from the endoplasmic reticulum into the endosomal system. During this manoeuvre, the interaction of li with class II serves to prevent premature association of antigenic peptide. Once the complex reaches the acidic environment of the endosomes, li is proteolytically degraded and dissociates, leaving the class II binding site available for binding antigenic peptide derived from exogenous proteins. The final Ii fragment to be displaced. CLIP (class II-associated invariant chain peptides), must be physically removed from the class II binding groove with assistance from another MHC-encoded molecule, DM. The interaction of DM with class II also aids in the subsequent rapid loading of high-affinity antigen-derived peptides into the MHC class II groove. The stable peptide-loaded complexes are now ready to exit the endocytic compartments to present their peptide antigen to specific T helper cells at the cell surface.

Animals↗

PubMed1997

A continuous central motif of invariant chain peptides, CLIP, is essential for binding to various I-A MHC class II molecules.

Invariant chain (li) associates with MHC class II molecules and performs a number of crucial functions in antigen presentation. A nested set of class II-associated li peptides (CLIP) has been isolated, comprising the li sequence between residues 82 and 107. Recently, X-ray crystallographic analysis has revealed that residues 87-101 occupy the HLA-DR3 peptide-binding groove. Based on our previous results, Lee and McConnell have also proposed a model for the binding of CLIP to various mouse I-A molecules in the binding groove. CLIP sequences are able to bind many MHC class II molecules but the molecular basis of this promiscuity has not yet been resolved. We have shown recently that CLIP binding to I-A class II molecules is generally tolerant to side chain substitutions, suggesting that the backbone structure of CLIP may provide the features critical for its interaction with class II. In pursuit of this, backbone stereochemical disruptions by serial D-alanine substitutions in CLIP86-104 have been used in competitive binding assays to I-A class II molecules. These studies have revealed that the phylogenetically conserved central continuous region, CLIP91-99, is intolerant to such configurational substitutions. Experiments with truncated and frame-shift analogues of CLIP showed that for effective binding to class II, the sequence element CLIP90-100 must be incorporated into a peptide of 13 or more residues including at least three residues N-terminal to this motif. Additionally, it appears that different I-A molecules accommodate CLIP in different binding frames. These investigations of the relationship between the structure and binding of CLIP analogues lead us to propose that there is a general backbone motif of a periodic nature within the CLIP sequence that minimizes deleterious contacts and allows promiscuous binding to class II molecules.

Amino Acid Sequence↗