CDR3 loop flexibility contributes to the degeneracy of TCR recognition

Reiser, Jean‐Baptiste; Darnault, Claudine; Grégoire, Claude; Mosser, Thomas; Mazza, Gilbert; Kearney, Alice; Merwe, P. Anton van der; Fontecilla‐Camps, Juan C.; Housset, D.; Malissen, Bernard

doi:10.1038/ni891

Cited by 243 publications

(212 citation statements)

References 53 publications

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“…However, at least some V-gene segments can use more than one set of interactions to bind a given MHC molecule. For example, two Vb2-containing TCRs with different peptide specificities show distinct docking footprints on the H-2K b a1 helix (Reiser et al 2000;Reiser et al 2003). The hypervariable CDR3 loops of the TCR and …”

Section: Structural Insights Into the Mechanism Of Mhc Restrictionmentioning

confidence: 99%

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

Wucherpfennig¹,

Gagnon²,

Call³

et al. 2010

Cold Spring Harbor Perspectives in Biology

152

108

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The T-cell receptor (TCR)-CD3 complex serves as a central paradigm for general principles of receptor assembly, ligand recognition, and signaling in the immune system. There is no other receptor system that matches the diversity of both receptor and ligand components. The recent expansion of the immunological structural database is beginning to identify key principles of MHC and peptide recognition. The multicomponent assembly of the TCR complex illustrates general principles used by many receptors in the immune system, which rely on basic and acidic transmembrane residues to guide assembly. The intrinsic binding of the cytoplasmic domains of the CD31 and z chains to the inner leaflet of the plasma membrane represents a novel mechanism for control of receptor activation: Insertion of critical CD31 tyrosines into the hydrophobic membrane core prevents their phosphorylation before receptor engagement. LIGAND BINDING BY THE EXTRACELLULAR DOMAINS OF T-CELL RECEPTORS: STRUCTURAL BASIS OF ab AND gd TCR BINDING TO A DIVERSE GROUP OF LIGANDST he structures of many T-cellreceptors (TCRs) in their ligand-bound state have now been determined, allowing some of the general rules of antigen recognition to be distilled. Though the best studied interaction is the binding of abTCR with peptide-MHC complexes, it is highly instructive to compare the prototypical binding to peptide-MHC with the recognition of lipid antigen-CD1 complexes and engagement of nonclassical MHC class I molecules by gdTCRs. These comparisons show that the recognition strategies for these

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Section: Structural Insights Into the Mechanism Of Mhc Restrictionmentioning

confidence: 99%

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

Wucherpfennig¹,

Gagnon²,

Call³

et al. 2010

Cold Spring Harbor Perspectives in Biology

152

108

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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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“…The high conformational flexibility of CDR often contributes to multispecificity of antigen recognition of TCR [24][25][26] and germline antibodies [27,28,31]. To find a role of unusually high conformational flexibility of the CDR H3 loop, we tested whether HzKR127 Fab makes any interaction with non-epitope regions of preS1.…”

Section: Resultsmentioning

confidence: 99%

Broadly neutralizing anti‐HBV antibody binds to non‐epitope regions of preS1

Chi

Kim

et al. 2009

FEBS Letters

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a b s t r a c tBroadly neutralizing anti-hepatitis B virus (HBV) antibody HzKR127 undergoes a fairly large conformational change of CDR H3 loop upon binding to HBV preS1 epitope peptide. In this study, we identified low-affinity antibody-binding sites in the largely unstructured preS1 region by nuclear magnetic resonance and biochemical studies, indicating that the antibody binds to the preS1 region outside the major immune epitope with low affinity. Surface plasma resonance experiments showed that the full-length preS1 has approximately three fold higher affinity for HzKR127 Fab than the preS1 epitope peptide, suggesting that the presence of low-affinity sites in the preS1 region increases the antibody-binding affinity. Therefore, the low-affinity binding of the antibody to non-epitope regions of preS1 may contribute to effective neutralization.

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CDR3 loop flexibility contributes to the degeneracy of TCR recognition

Cited by 243 publications

References 53 publications

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

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

Broadly neutralizing anti‐HBV antibody binds to non‐epitope regions of preS1

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CDR3 loop flexibility contributes to the degeneracy of TCR recognition

Cited by 243 publications

References 53 publications

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

Structural Biology of the T-cell Receptor: Insights into Receptor Assembly, Ligand Recognition, and Initiation of Signaling

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

Broadly neutralizing anti‐HBV antibody binds to non‐epitope regions of preS1

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