A T Cell Receptor CDR3β Loop Undergoes Conformational Changes of Unprecedented Magnitude Upon Binding to a Peptide/MHC Class I Complex

Reiser, Jean‐Baptiste; Grégoire, Claude; Darnault, Claudine; Mosser, Thomas; Guimezanes, Annick; Schmitt-Verhulst, Anne-Marie; Fontecilla‐Camps, Juan C.; Mazza, Gilbert; Malissen, Bernard; Housset, D.

doi:10.1016/s1074-7613(02)00288-1

Cited by 198 publications

(159 citation statements)

References 55 publications

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“…However, due to the exceptional length of the 14-mer peptide, the conformational adaptation might be limited and could possibly not adjust to a flat antigenic surface as the CASP8/HLA-B*3501 complex. Therefore, even more dramatic structural reorganizations of the CDRs of the TCR than observed previously upon peptide/MHC binding (up to 15 Å) (11,20,36) might be expected.…”

Section: Discussionmentioning

confidence: 85%

Conformational Restraints and Flexibility of 14-Meric Peptides in Complex with HLA-B*3501

Probst‐Kepper

Hecht

Herrmann³

et al. 2004

The Journal of Immunology

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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 Å 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 α-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.

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Section: Discussionmentioning

confidence: 85%

Conformational Restraints and Flexibility of 14-Meric Peptides in Complex with HLA-B*3501

Probst‐Kepper

Hecht

Herrmann³

et al. 2004

The Journal of Immunology

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“…15,16 The available crystal structures of liganded and unliganded TCRs have implied that the flexibility of the TCR combining site facilitates TCR adaptation to rather conformationally constrained MHC-peptide surfaces. [27][28][29] Based on the SH3 work, 25,26 the importance of the affinity for peptide binding promiscuity has been highlighted, and such interactions tend, as might be expected, to be of low affinity. In accordance, our peptide-antibodies displayed affinities in the lM range, which for antibodies means low-affinity interactions.…”

Section: Discussionmentioning

confidence: 99%

Epitope‐specificity of recombinant antibodies reveals promiscuous peptide‐binding properties

et al. 2012

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Protein-peptide interactions are a common occurrence and essential for numerous cellular processes, and frequently explored in broad applications within biology, medicine, and proteomics. Therefore, understanding the molecular mechanism(s) of protein-peptide recognition, specificity, and binding interactions will be essential. In this study, we report the first detailed analysis of antibody-peptide interaction characteristics, by combining large-scale experimental peptide binding data with the structural analysis of eight human recombinant antibodies and numerous peptides, targeting tryptic mammalian and eukaryote proteomes. The results consistently revealed that promiscuous peptide-binding interactions, that is, both specific and degenerate binding, were exhibited by all antibodies, and the discovery was corroborated by orthogonal data, indicating that this might be a general phenomenon for low-affinity antibodypeptide interactions. The molecular mechanism for the degenerate peptide-binding specificity appeared to be executed through the use of 2-3 semi-conserved anchor residues in the C-terminal part of the peptides, in analogue to the mechanism utilized by the major histocompatibility complex-peptide complexes. In the long-term, this knowledge will be instrumental for advancing our fundamental understanding of protein-peptide interactions, as well as for designing, generating, and applying peptide specific antibodies, or peptide-binding proteins in general, in various biotechnical and medical applications.

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“…As discussed above, the elementary steps of association of soluble pMHC with the TCR have not been resolved so far, yet it is assumed to proceed at a relatively slow rate due to conformation transitions in the TCR binding site [43][44][45][46]. The latter are apparently central for attaining high specificity in the antigen recognition.…”

Section: Mechanism Of Pmhc Association With T-cellsmentioning

confidence: 99%

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells

Pecht

Gakamsky

2005

FEBS Letters

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The interactions between the TCR and peptides bound to class I MHC encoded molecules (pMHC) and a mechanism for CD8 cooperation in this process are reviewed. Observation of two TCR/CD8 populations with different lateral diffusion rate constants as well as two distinct association phases of class I MHC tetramers ((pMHC) 4 ) with T-cells suggest that the most efficient pMHC-T-cell association route corresponds to a fast tetramer binding to a colocalized CD8/TCR population, which apparently resides within membrane rafts. Thus, ligandcell association starts by pMHC binding to the CD8. This rather fast step promotes pMHC association with CD8-proximal TCRs and thereby enhances the overall association process. The model suggests that this raft-associated CD8-TCR subpopulation is responsible for evoking T-cell activation.

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A T Cell Receptor CDR3β Loop Undergoes Conformational Changes of Unprecedented Magnitude Upon Binding to a Peptide/MHC Class I Complex

Cited by 198 publications

References 55 publications

Conformational Restraints and Flexibility of 14-Meric Peptides in Complex with HLA-B*3501

Conformational Restraints and Flexibility of 14-Meric Peptides in Complex with HLA-B*3501

Epitope‐specificity of recombinant antibodies reveals promiscuous peptide‐binding properties

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells

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A T Cell Receptor CDR3β Loop Undergoes Conformational Changes of Unprecedented Magnitude Upon Binding to a Peptide/MHC Class I Complex

Cited by 198 publications

References 55 publications

Conformational Restraints and Flexibility of 14-Meric Peptides in Complex with HLA-B*3501

Conformational Restraints and Flexibility of 14-Meric Peptides in Complex with HLA-B*3501

Epitope‐specificity of recombinant antibodies reveals promiscuous peptide‐binding properties

Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8+ T‐cells

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Product

Resources

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Spatial coordination of CD8 and TCR molecules controls antigen recognition by CD8⁺ T‐cells