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Human HLA-B*3501 binds an antigenic peptide of 14-aa length derived from an alternative reading frame of M-CSF with high affinity. Due to its extraordinary length, the exact HLA binding mode was unpredictable. The crystal structure of HLA-B*3501 at 1.5 A shows that the N and C termini of the peptide are embedded in the A and F pockets, respectively, similar to a peptide of normal length. The central part of the 14-meric peptide bulges flexibly out of the groove. Two variants of the alternative reading frame of M-CSF peptide substituted at P2 or P2 and P9 with Ala display weak or no T cell activation. Their structure differs mainly in flexibility and conformation from the agonistic peptide. Moreover, the variants induce subtle changes of MHC alpha-helical regions implicated as critical for TCR contact. The TCR specifically recognizing this peptide/MHC complex exhibits CDR3 length within the normal range, suggesting major conformational adaptations of this receptor upon peptide/MHC binding. Thus, the potential antigenic repertoire recognizable by CTLs is larger than currently thought.

Type

Journal article

Journal

J Immunol

Publication Date

01/11/2004

Volume

173

Pages

5610 - 5616

Keywords

Alanine, Amino Acid Sequence, Amino Acid Substitution, Antigen Presentation, Clone Cells, Crystallography, X-Ray, HLA-B35 Antigen, Humans, Macromolecular Substances, Macrophage Colony-Stimulating Factor, Molecular Sequence Data, Peptide Fragments, Protein Binding, Protein Conformation, Protein Structure, Secondary, Receptors, Antigen, T-Cell, alpha-beta, T-Lymphocytes, Cytotoxic