Conformational restraints and flexibility of 14-meric peptides in complex with HLA-B*3501

Probst-Kepper, Michael [Hannover Medical School, Hannover, Germany & German Research Centre for Biotechnology, Braunschweig, Germany] Hecht, Hans-Jürgen [German Research Centre for Biotechnology, Braunschweig, Germany] Herrmann, Hanne [German Research Centre for Biotechnology, Braunschweig, Germany] Janke, Viktoria [Hannover Medical School, Hannover, Germany] Ocklenburg, Frank [Hannover Medical School, Hannover, Germany] Klempnauer, Jürgen [Hannover Medical School, Hannover, Germany] Van den Eynde, Benoît [UCL] Weiss, Siegfried [German Research Centre for Biotechnology, Braunschweig, Germany] et al.[show all]

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.