Structural and functional consequences of altering a peptide MHC anchor residue

G. J. Kersh, M. J. Miley, C. A. Nelson, A. Grakoui, S. Horvath, D. L. Donermeyer, J. Kappler, P. M. Allen, D. H. Fremont

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95 Scopus citations

Abstract

To better understand TCR discrimination of multiple ligands, we have analyzed the crystal structures of two Hb peptide/I-Ek complexes that differ by only a single amino acid substitution at the P6 anchor position within the peptide (E73D). Detailed comparison of multiple independently determined structures at 1.9 Å resolution reveals that removal of a single buried methylene group can alter a critical portion of the TCR recognition surface. Significant variance was observed in the peptide P5-P8 main chain as well as a rotamer difference at LeuP8, ∼10 Å distal from the substitution. No significant variations were observed in the conformation of the two MHC class II molecules. The ligand alteration results in two peptide/MHC complexes that generate bulk T cell responses that are distinct and essentially nonoverlapping. For the Hb-specific T cell 3.L2, substitution reduces the potency of the ligand 1000-fold. Soluble 3.L2 TCR binds the two peptide/MHC complexes with similar affinity, although with faster kinetics. These results highlight the role of subtle variations in MHC Ag presentation on T cell activation and signaling.

Original languageEnglish
Pages (from-to)3345-3354
Number of pages10
JournalJournal of Immunology
Volume166
Issue number5
DOIs
StatePublished - Mar 1 2001

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