Differential utilization of binding loop flexibility in T cell receptor ligand selection and cross-reactivity

Ayres, Cory M.; Scott, Daniel R.; Corcelli, Steven A.; Baker, Brian M.

doi:10.1038/srep25070

Cited by 23 publications

(33 citation statements)

References 58 publications

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“…As expected based on previous work, 18 we observed no clear correlations between Cα fluctuations and raw or normalized temperature factors (correlation coefficients of 0.15 and 0.24, respectively). This is expected as temperature factors generally report poorly on fast atomic motions in protein structures.…”

Section: Resultssupporting

confidence: 87%

Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition

Ayres

Riley

Corcelli

et al. 2017

J. Chem. Inf. Model.

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In cellular immunity, T cells recognize peptide antigens bound and presented by major histocompatibility complex (MHC) proteins. The motions of peptides bound to MHC play a significant role in determining immunogenicity. However, existing approaches for investigating peptide/MHC motional dynamics are challenging or of low throughput, hindering the development of algorithms for predicting immunogenicity from large databases, such as those of tumor or genetically unstable viral genomes. We addressed this by performing exhaustive molecular dynamics simulations on a large structural database of peptides bound to the most commonly expressed human class I MHC protein, HLA-A*0201. The simulations reproduced experimental indicators of motion and were used to generate simple models for predicting site-specific, rapid motions of bound peptides through differences in their sequence and chemical composition alone. The models can easily be applied on their own or incorporated into immunogenicity prediction algorithms. Beyond their predictive power, the models provided insight into how amino acid substitutions can influence peptide and protein motions and how dynamic information is communicated across peptides. They also indicate a link between peptide rigidity and hydrophobicity, two features known to be important in influencing cellular immune responses.

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Section: Resultssupporting

confidence: 87%

Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition

Ayres

Riley

Corcelli

et al. 2017

J. Chem. Inf. Model.

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“…The HCV1406 TCR which recognizes the HCV NS3 epitope requires a lysine at P1, which is also engaged by CDR1α (35). Lastly, the flexibility inherent to some TCRs (65) may permit different hot spots with different ligands, as is believed to occur the well-studied TCR 2C (66, 67). …”

Section: Rationalizing the Specificity/cross-reactivity Duality Of Tcrsmentioning

confidence: 99%

Emerging Concepts in TCR Specificity: Rationalizing and (Maybe) Predicting Outcomes

Singh

Riley

Baker

et al. 2017

The Journal of Immunology

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T cell specificity emerges from a myriad of processes, ranging from the biological pathways that control T cell signaling to the structural and physical mechanisms that influence how TCRs bind antigen/MHC. Of these processes, the binding specificity of the TCR is a key component. However, TCR specificity is enigmatic: TCRs are at once specific but also cross-reactive. Although long-appreciated, this duality continues to puzzle immunologists and has implications for the development of TCR-based therapeutics. Here we review TCR specificity, emphasizing results that have emerged from structural and physical studies of TCR binding. We show how the TCR specificity/cross-reactivity duality can be rationalized from structural and biophysical principles. There is excellent agreement between predictions from these principles and classic predictions about the scope of TCR cross-reactivity. We demonstrate how these same principles can also explain amino acid preferences in immunogenic epitopes and highlight opportunities for structural considerations in predictive immunology.

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“…It remains difficult to identify thermodynamic signatures in the TCR/pMHC complex formation, as its trimolecular nature translates into a wide range of entropic cost vs intermolecular contacts contributions. This has outcomes in TCR degeneracy and cross‐reactivity …”

Section: Resultsmentioning

confidence: 99%

The 3A6‐TCR/superagonist/HLA‐DR2a complex shows similar interface and reduced flexibility compared to the complex with self‐peptide

2019

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T‐cell receptor (TCR) recognition of the myelin basic protein (MBP) peptide presented by major histocompatibility complex (MHC) protein HLA‐DR2a, one of the MHC class II alleles associated with multiple sclerosis, is highly variable. Interactions in the trimolecular complex between the TCR of the MBP83‐99‐specific T cell clone 3A6 with the MBP‐peptide/HLA‐DR2a (abbreviated TCR/pMHC) lead to substantially different proliferative responses when comparing the wild‐type decapeptide MBP90‐99 and a superagonist peptide, which differs mainly in the residues that point toward the TCR. Here, we investigate the influence of the peptide sequence on the interface and intrinsic plasticity of the TCR/pMHC trimolecular and pMHC bimolecular complexes by molecular dynamics simulations. The intermolecular contacts at the TCR/pMHC interface are similar for the complexes with the superagonist and the MBP self‐peptide. The orientation angle between TCR and pMHC fluctuates less in the complex with the superagonist peptide. Thus, the higher structural stability of the TCR/pMHC tripartite complex with the superagonist peptide, rather than a major difference in binding mode with respect to the self‐peptide, seems to be responsible for the stronger proliferative response.

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Differential utilization of binding loop flexibility in T cell receptor ligand selection and cross-reactivity

Cited by 23 publications

References 58 publications

Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition

Modeling Sequence-Dependent Peptide Fluctuations in Immunologic Recognition

Emerging Concepts in TCR Specificity: Rationalizing and (Maybe) Predicting Outcomes

The 3A6‐TCR/superagonist/HLA‐DR2a complex shows similar interface and reduced flexibility compared to the complex with self‐peptide

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