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.
Weenink
S M
SM
Human Genetics Group, John Curtin School of Medical Research, The Australian National University, Canberra.
Milburn
P J
PJ
Gautam
A M
AM
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism*; D001665:Binding Sites / Q000276:immunology; D002460:Cell Line; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000276:immunology
D000944:Antigens, Differentiation, B-Lymphocyte; D000939:Epitopes; D000949:Histocompatibility Antigens Class II; C045084:invariant chain