Cutting Edge: TCR Contacts as Anchors: Effects on Affinity and HLA-DM Stability

Anderson, Matthew W.; Gorski, Jack

doi:10.4049/jimmunol.171.11.5683

Cited by 22 publications

(35 citation statements)

References 32 publications

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“…Through this approach, one can construct a series of higher order mutant cycles to analyze the impact of different peptide substitutions relative to the wt HA sequence on complex energetics. We have previously tested the hypothesis that epitope selection is a distributive process (27) and we have recently observed that peptide binding is highly cooperative for peptides substituted in residues showing intermediate solvent accessibility (15). We interpreted our results in terms of disruption of the H-bond network at these positions.…”

Section: Discussionmentioning

confidence: 57%

Cooperativity of Hydrophobic Anchor Interactions: Evidence for Epitope Selection by MHC Class II as a Folding Process

Ferrante

Gorski

2007

The Journal of Immunology

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Peptide binding to MHC class II (MHCII) molecules is stabilized by hydrophobic anchoring and hydrogen bond formation. We view peptide binding as a process in which the peptide folds into the binding groove and to some extent the groove folds around the peptide. Our previous observation of cooperativity when analyzing binding properties of peptides modified at side chains with medium to high solvent accessibility is compatible with such a view. However, a large component of peptide binding is mediated by residues with strong hydrophobic interactions that bind to their respective pockets. If these reflect initial nucleation events they may be upstream of the folding process and not show cooperativity. To test whether the folding hypothesis extends to these anchor interactions, we measured dissociation and affinity to HLA-DR1 of an influenza hemagglutinin-derived peptide with multiple substitutions at major anchor residues. Our results show both negative and positive cooperative effects between hydrophobic pocket interactions. Cooperativity was also observed between hydrophobic pockets and positions with intermediate solvent accessibility, indicating that hydrophobic interactions participate in the overall folding process. These findings point out that predicting the binding potential of epitopes cannot assume additive and independent contributions of the interactions between major MHCII pockets and corresponding peptide side chains.

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Section: Discussionmentioning

confidence: 57%

Cooperativity of Hydrophobic Anchor Interactions: Evidence for Epitope Selection by MHC Class II as a Folding Process

Ferrante

Gorski

2007

The Journal of Immunology

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“…68 It has also been shown that substitutions of T-cell contact residues that flank anchor residues in HA(306-318) affect peptide binding stability with DR1 even though the substituted residues do not directly contact protein. 69 It was proposed that the substitutions might alter the disposition of neighboring residues or hydrogen bonds. Similar interactions of neighboring residues, perhaps communicated through small deviations in the positioning or dynamics of the main chain, may cause the context-dependent effects observed in this study.…”

Section: Discussionmentioning

confidence: 99%

Energetics and Cooperativity of the Hydrogen Bonding and Anchor Interactions that Bind Peptides to MHC Class II Protein

McFarland

Katz

Sant

et al. 2005

Journal of Molecular Biology

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“…It is tempting to speculate that this provides a link between peptide selection by the MHC and subsequent TCR selection by the peptide-MHC complex. Non-anchor peptide positions that simultaneously influence both peptide and TCR binding have been found in other class I systems (19,55), and solventexposed potential TCR contact positions have been shown to influence peptide binding in a class II system (44). However, whether this dual recognition is physiologically relevant in terms of simultaneous peptide and T cell receptor selection by the MHC molecule is unknown.…”

Section: Discussionmentioning

confidence: 99%

Strategic Mutations in the Class I Major Histocompatibility Complex HLA-A2 Independently Affect Both Peptide Binding and T Cell Receptor Recognition

Baxter¹,

Gagnon

Davis-Harrison³

et al. 2004

Journal of Biological Chemistry

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Mutational studies of T cell receptor (TCR) contact residues on the surface of the human class I major histocompatibility complex (MHC) molecule HLA-A2 have identified a "functional hot spot" that comprises Arg 65 and Lys 66 and is involved in recognition by most peptide-specific HLA-A2-restricted TCRs. Although there is a significant amount of functional data on the effects of mutations at these positions, there is comparatively little biochemical information that could illuminate their mode of action. Here, we have used a combination of fluorescence anisotropy, functional assays, and Biacore binding experiments to examine the effects of mutations at these positions on the peptide-MHC interaction and TCR recognition. The results indicate that mutations at both position 65 and position 66 influence peptide binding by HLA-A2 to various extents. In particular, mutations at position 66 result in significantly increased peptide dissociation rates. However, these effects are independent of their effects on TCR recognition, and the Arg 65 -Lys 66 region thus represents a true "hot spot" for TCR recognition. We also made the observation that in vitro T cell reactivity does not scale with the half-life of the peptide-MHC complex, as is often assumed. Finally, position 66 is implicated in the "dual recognition" of both peptide and TCR, emphasizing the multiple roles of the class I MHC peptide-binding domain.Recognition of a peptide bound to a major histocompatibility complex protein (peptide-MHC) 1 by the ␣␤ T cell receptor (TCR) is necessary for the initiation and propagation of a cellular immune response, as well as the development and maintenance of the T cell repertoire. TCRs bind peptide-MHC in a diagonal-to-orthogonal fashion, interacting with elements of both the peptide and the MHC (1-3). Numerous studies have probed the interfaces between TCRs and their ligands through the use of altered peptides or site-directed mutagenesis of the MHC (e.g. see . These studies have been useful in identifying hot spots within individual interfaces, as well as predicting the biophysical mechanisms by which T cell receptors bind their ligand (9).In our studies of TCR recognition of the human class I MHC HLA-A*0201 (referred to as HLA-A2) presenting the Tax peptide (sequence LLFGYPVYV; see Ref. 10), we identified a functional hot spot consisting of arginine 65 and lysine 66 on the HLA-A2 ␣1 helix (4). In a mutagenesis experiment involving 15 HLA-A2 amino acids contacted by the Tax-HLA-A2-specific ␣␤ T cell receptor A6, only two mutations, Arg 65 3 Ala (R65A) and Lys 66 3 Ala (K66A), resulted in significantly reduced T cell effector functions when the mutants were used to present the Tax peptide to T cells expressing the A6 receptor. Similar results were found with T cells expressing a different Tax-HLA-A2-specific TCR, B7. Lys 66 was also identified as a critical position influencing T cell reactivity in at least one other mutagenesis study of HLA-A2 (8).The general nature of the Arg 65 -Lys 66 hot spot in the recognition of Tax...

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Cutting Edge: TCR Contacts as Anchors: Effects on Affinity and HLA-DM Stability

Cited by 22 publications

References 32 publications

Cooperativity of Hydrophobic Anchor Interactions: Evidence for Epitope Selection by MHC Class II as a Folding Process

Cooperativity of Hydrophobic Anchor Interactions: Evidence for Epitope Selection by MHC Class II as a Folding Process

Energetics and Cooperativity of the Hydrogen Bonding and Anchor Interactions that Bind Peptides to MHC Class II Protein

Strategic Mutations in the Class I Major Histocompatibility Complex HLA-A2 Independently Affect Both Peptide Binding and T Cell Receptor Recognition

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