Amino-terminal flanking residues determine the conformation of a peptide-class II MHC complex.
The peptide spanning residues 48-62 of hen egg white lysozyme presented by I-A(k) molecules gives rise to two T cell populations, types A and B, that recognize distinct conformers of the complex generated in late and recycling endosomes. The class II-like accessory molecule H2-DM functions as a conformational editor, eliminating the type B conformer in late endosomes. Here, we show that the conformation of the complex, and its susceptibility to editing by H2-DM, are determined by peptide amino-terminal flanking residues. Elimination of these residues abolished editing, permitting formation of the type B conformer in late endosomes. Substitutions at P(-2) affected the stability of the type B conformer, preventing its formation and/or editing, without hindering peptide binding or formation of the type A conformer of the complex. We conclude that interactions involving amino-terminal flanking residues stabilize peptide-MHC conformers and confer resistance to editing by H2-DM, influencing the nature of the T cell repertoire.
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Scott B
SB
Lovitch
Zheng
Z
Pu
Emil R
ER
Unanue
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D006825:Hybridomas; D008081:Liposomes; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation
D000949:Histocompatibility Antigens Class II; D008081:Liposomes; D010446:Peptide Fragments