International Immunology, Vol 9, 317-325, Copyright © 1997 by Oxford University Press
SM Weenink, PJ Milburn and AM Gautam
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.
ARTICLES
A continuous central motif of invariant chain peptides, CLIP, is essential for binding to various I-A MHC class II molecules
Human Genetics Group, John Curtin School of Medical Research, The Australian National University, Canberra.
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