Conformational Restraints and Flexibility of 14-Meric Peptides in Complex with HLA-B3501

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...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2004-11, Vol.173 (9), p.5610-5616
Main Authors: Probst-Kepper, Michael, Hecht, Hans-Jurgen, Herrmann, Hanne, Janke, Viktoria, Ocklenburg, Frank, Klempnauer, Jurgen, van den Eynde, Benoit J, Weiss, Siegfried
Format: Article
Language:English
Subjects:
Alanine - chemistry
Amino Acid Sequence
Amino Acid Substitution - immunology
Antigen Presentation
Clone Cells
Crystallography, X-Ray
HLA-B35 Antigen - chemistry
HLA-B35 Antigen - immunology
HLA-B35 Antigen - metabolism
Humans
Macromolecular Substances
Macrophage Colony-Stimulating Factor - chemistry
Macrophage Colony-Stimulating Factor - immunology
Macrophage Colony-Stimulating Factor - metabolism
Molecular Sequence Data
Peptide Fragments - chemistry
Peptide Fragments - immunology
Peptide Fragments - metabolism
Protein Binding - immunology
Protein Conformation
Protein Structure, Secondary
Receptors, Antigen, T-Cell, alpha-beta - chemistry
Receptors, Antigen, T-Cell, alpha-beta - metabolism
T-Lymphocytes, Cytotoxic - immunology
T-Lymphocytes, Cytotoxic - metabolism
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Description
Summary: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.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.173.9.5610