Binding of longer peptides to the H-2Kb heterodimer is restricted to peptides extended at their C terminus: refinement of the inherent MHC class I peptide binding criteria.
MHC class I molecules usually bind short peptides of 8-10 amino acids, and binding is dependent on allele-specific anchor residues. However, in a number of cellular systems, class I molecules have been found containing peptides longer than the canonical size. To understand the structural requirements for MHC binding of longer peptides, we used an in vitro class I MHC folding assay to examine peptide variants of the antigenic VSV 8 mer core peptide containing length extensions at either their N or C terminus. This approach allowed us to determine the ability of each peptide to productively form Kb/beta2-microglobulin/peptide complexes. We found that H-2Kb molecules can accommodate extended peptides, but only if the extension occurs at the C-terminal peptide end, and that hydrophobic flanking regions are preferred. Peptides extended at their N terminus did not promote productive formation of the trimolecular complex. A structural basis for such findings comes from molecular modeling of a H-2Kb/12 mer complex and comparative analysis of MHC class I structures. These analyses revealed that structural constraints in the A pocket of the class I peptide binding groove hinder the binding of N-terminal-extended peptides, whereas structural features at the C-terminal peptide residue pocket allow C-terminal peptide extensions to reach out of the cleft. These findings broaden our understanding of the inherent peptide binding and epitope selection criteria of the MHC class I molecule. Core peptides extended at their N terminus cannot bind, but peptide extensions at the C terminus are tolerated.
Hörig
H
H
Department of Microbiology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Young
A C
AC
Papadopoulos
N J
NJ
DiLorenzo
T P
TP
Nathenson
S G
SG
D000818:Animals; D003198:Computer Simulation; D019281:Dimerization; D015195:Drug Design; D004734:Energy Metabolism; D006183:H-2 Antigens / Q000737:chemistry / Q000378:metabolism*; D046911:Macromolecular Substances; D051379:Mice; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D017510:Protein Folding; D013329:Structure-Activity Relationship
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D046911:Macromolecular Substances; D009842:Oligopeptides; D010446:Peptide Fragments