Conformational restraints and flexibility of 14-meric peptides in complex with HLA-B*3501.
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.
Probst-Kepper
Michael
M
Department of Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany. probst-kepper.michael@mh-hannover.de
Hecht
Hans-Jürgen
HJ
Herrmann
Hanne
H
Janke
Viktoria
V
Ocklenburg
Frank
F
Klempnauer
Jürgen
J
van den Eynde
Benoit J
BJ
Weiss
Siegfried
S
D000409:Alanine / Q000737:chemistry; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000276:immunology; D017951:Antigen Presentation; D002999:Clone Cells; D018360:Crystallography, X-Ray; D015797:HLA-B35 Antigen / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D046911:Macromolecular Substances; D016173:Macrophage Colony-Stimulating Factor / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism
D015797:HLA-B35 Antigen; D046911:Macromolecular Substances; D010446:Peptide Fragments; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016173:Macrophage Colony-Stimulating Factor; D000409:Alanine