TCR-induced alteration of primary MHC peptide anchor residue

Florian Madura; Pierre J. Rizkallah; Mateusz Legut; Christopher J. Holland; Anna Fuller; Anna Bulek; Andrea J. Schauenburg; Andrew Trimby; Jade R. Hopkins; Stephen A. Wells; Andrew Godkin; John J. Miles; Malkit Sami; Yi Li; Nathaniel Liddy; Bent K. Jakobsen; E. Joel Loveridge; David K. Cole; Andrew K. Sewell

doi:10.1002/eji.201948085

TCR-induced alteration of primary MHC peptide anchor residue

Florian Madura, Pierre J. Rizkallah, Mateusz Legut, Christopher J. Holland, Anna Fuller, Anna Bulek, Andrea J. Schauenburg, Andrew Trimby, Jade R. Hopkins, Stephen A. Wells, Andrew Godkin, John J. Miles, Malkit Sami, Yi Li, Nathaniel Liddy, Bent K. Jakobsen, E. Joel Loveridge, David K. Cole, Andrew K. Sewell

Department of Chemical Engineering

Research output: Contribution to journal › Article › peer-review

22 Citations (SciVal)

Abstract

The HLA-A*02:01-restricted decapeptide EAAGIGILTV, derived from melanoma antigen recognized by T-cells-1 (MART-1) protein, represents one of the best-studied tumor associated T-cell epitopes, but clinical results targeting this peptide have been disappointing. This limitation may reflect the dominance of the nonapeptide, AAGIGILTV, at the melanoma cell surface. The decapeptide and nonapeptide are presented in distinct conformations by HLA-A*02:01 and TCRs from clinically relevant T-cell clones recognize the nonapeptide poorly. Here, we studied the MEL5 TCR that potently recognizes the nonapeptide. The structure of the MEL5-HLA-A*02:01-AAGIGILTV complex revealed an induced fit mechanism of antigen recognition involving altered peptide–MHC anchoring. This “flexing” at the TCR–peptide–MHC interface to accommodate the peptide antigen explains previously observed incongruences in this well-studied system and has important implications for future therapeutic approaches. Finally, this study expands upon the mechanisms by which molecular plasticity can influence antigen recognition by T cells.

Original language	English
Pages (from-to)	1052-1066
Number of pages	15
Journal	European Journal of Immunology
Volume	49
Issue number	7
Early online date	15 May 2019
DOIs	https://doi.org/10.1002/eji.201948085
Publication status	Published - 1 Jul 2019

Funding

Acknowledgements: The authors would like to thank Diamond Light Source for beam time (proposal mx4352-1 and mx6232-10), and the staff of beamlines I04-1 and I03 for assistance with crystal testing and data collection. This work was funded by Wellcome and used equipment and reagents purchased by UK Biotechnology and Biological Sciences Research Council (Grant BB/H001085/1). A.K.S. is a Wellcome Senior Investigator (WT086716MA). D.K.C. was a Wellcome Career Development Fellow (WT095767). S.A.W. has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement No 648283 “GROWMOF”).

Keywords

crystal structure
MART-1/Melan-A
peptide–major histocompatibility complex (pMHC)
surface plasmon resonance (SPR)
T cell: T-cell receptor (TCR)

ASJC Scopus subject areas

Immunology and Allergy
Immunology

Access to Document

10.1002/eji.201948085Licence: CC BY

Cite this

Madura, F., Rizkallah, P. J., Legut, M., Holland, C. J., Fuller, A., Bulek, A., Schauenburg, A. J., Trimby, A., Hopkins, J. R., Wells, S. A., Godkin, A., Miles, J. J., Sami, M., Li, Y., Liddy, N., Jakobsen, B. K., Loveridge, E. J., Cole, D. K., & Sewell, A. K. (2019). TCR-induced alteration of primary MHC peptide anchor residue. European Journal of Immunology, 49(7), 1052-1066. https://doi.org/10.1002/eji.201948085

Madura, F, Rizkallah, PJ, Legut, M, Holland, CJ, Fuller, A, Bulek, A, Schauenburg, AJ, Trimby, A, Hopkins, JR, Wells, SA, Godkin, A, Miles, JJ, Sami, M, Li, Y, Liddy, N, Jakobsen, BK, Loveridge, EJ, Cole, DK & Sewell, AK 2019, 'TCR-induced alteration of primary MHC peptide anchor residue', European Journal of Immunology, vol. 49, no. 7, pp. 1052-1066. https://doi.org/10.1002/eji.201948085

@article{5a4f440c75f4466f92c997b7ed71bd13,

title = "TCR-induced alteration of primary MHC peptide anchor residue",

abstract = "The HLA-A*02:01-restricted decapeptide EAAGIGILTV, derived from melanoma antigen recognized by T-cells-1 (MART-1) protein, represents one of the best-studied tumor associated T-cell epitopes, but clinical results targeting this peptide have been disappointing. This limitation may reflect the dominance of the nonapeptide, AAGIGILTV, at the melanoma cell surface. The decapeptide and nonapeptide are presented in distinct conformations by HLA-A*02:01 and TCRs from clinically relevant T-cell clones recognize the nonapeptide poorly. Here, we studied the MEL5 TCR that potently recognizes the nonapeptide. The structure of the MEL5-HLA-A*02:01-AAGIGILTV complex revealed an induced fit mechanism of antigen recognition involving altered peptide–MHC anchoring. This “flexing” at the TCR–peptide–MHC interface to accommodate the peptide antigen explains previously observed incongruences in this well-studied system and has important implications for future therapeutic approaches. Finally, this study expands upon the mechanisms by which molecular plasticity can influence antigen recognition by T cells.",

keywords = "crystal structure, MART-1/Melan-A, peptide–major histocompatibility complex (pMHC), surface plasmon resonance (SPR), T cell: T-cell receptor (TCR)",

author = "Florian Madura and Rizkallah, \{Pierre J.\} and Mateusz Legut and Holland, \{Christopher J.\} and Anna Fuller and Anna Bulek and Schauenburg, \{Andrea J.\} and Andrew Trimby and Hopkins, \{Jade R.\} and Wells, \{Stephen A.\} and Andrew Godkin and Miles, \{John J.\} and Malkit Sami and Yi Li and Nathaniel Liddy and Jakobsen, \{Bent K.\} and Loveridge, \{E. Joel\} and Cole, \{David K.\} and Sewell, \{Andrew K.\}",

year = "2019",

month = jul,

day = "1",

doi = "10.1002/eji.201948085",

language = "English",

volume = "49",

pages = "1052--1066",

journal = "European Journal of Immunology",

issn = "0014-2980",

publisher = "Wiley-VCH Verlag",

number = "7",

}

TY - JOUR

T1 - TCR-induced alteration of primary MHC peptide anchor residue

AU - Madura, Florian

AU - Rizkallah, Pierre J.

AU - Legut, Mateusz

AU - Holland, Christopher J.

AU - Fuller, Anna

AU - Bulek, Anna

AU - Schauenburg, Andrea J.

AU - Trimby, Andrew

AU - Hopkins, Jade R.

AU - Wells, Stephen A.

AU - Godkin, Andrew

AU - Miles, John J.

AU - Sami, Malkit

AU - Li, Yi

AU - Liddy, Nathaniel

AU - Jakobsen, Bent K.

AU - Loveridge, E. Joel

AU - Cole, David K.

AU - Sewell, Andrew K.

PY - 2019/7/1

Y1 - 2019/7/1

N2 - The HLA-A*02:01-restricted decapeptide EAAGIGILTV, derived from melanoma antigen recognized by T-cells-1 (MART-1) protein, represents one of the best-studied tumor associated T-cell epitopes, but clinical results targeting this peptide have been disappointing. This limitation may reflect the dominance of the nonapeptide, AAGIGILTV, at the melanoma cell surface. The decapeptide and nonapeptide are presented in distinct conformations by HLA-A*02:01 and TCRs from clinically relevant T-cell clones recognize the nonapeptide poorly. Here, we studied the MEL5 TCR that potently recognizes the nonapeptide. The structure of the MEL5-HLA-A*02:01-AAGIGILTV complex revealed an induced fit mechanism of antigen recognition involving altered peptide–MHC anchoring. This “flexing” at the TCR–peptide–MHC interface to accommodate the peptide antigen explains previously observed incongruences in this well-studied system and has important implications for future therapeutic approaches. Finally, this study expands upon the mechanisms by which molecular plasticity can influence antigen recognition by T cells.

AB - The HLA-A*02:01-restricted decapeptide EAAGIGILTV, derived from melanoma antigen recognized by T-cells-1 (MART-1) protein, represents one of the best-studied tumor associated T-cell epitopes, but clinical results targeting this peptide have been disappointing. This limitation may reflect the dominance of the nonapeptide, AAGIGILTV, at the melanoma cell surface. The decapeptide and nonapeptide are presented in distinct conformations by HLA-A*02:01 and TCRs from clinically relevant T-cell clones recognize the nonapeptide poorly. Here, we studied the MEL5 TCR that potently recognizes the nonapeptide. The structure of the MEL5-HLA-A*02:01-AAGIGILTV complex revealed an induced fit mechanism of antigen recognition involving altered peptide–MHC anchoring. This “flexing” at the TCR–peptide–MHC interface to accommodate the peptide antigen explains previously observed incongruences in this well-studied system and has important implications for future therapeutic approaches. Finally, this study expands upon the mechanisms by which molecular plasticity can influence antigen recognition by T cells.

KW - crystal structure

KW - MART-1/Melan-A

KW - peptide–major histocompatibility complex (pMHC)

KW - surface plasmon resonance (SPR)

KW - T cell: T-cell receptor (TCR)

UR - https://www.scopus.com/pages/publications/85068264205

U2 - 10.1002/eji.201948085

DO - 10.1002/eji.201948085

M3 - Article

C2 - 31091334

AN - SCOPUS:85068264205

SN - 0014-2980

VL - 49

SP - 1052

EP - 1066

JO - European Journal of Immunology

JF - European Journal of Immunology

IS - 7

ER -

TCR-induced alteration of primary MHC peptide anchor residue

Abstract

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Avance 300 MHz Nuclear Magnetic Resonance (NMR) Spectrometer (1South)

Cite this

TCR-induced alteration of primary MHC peptide anchor residue

Abstract

Funding

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Equipment

Avance 300 MHz Nuclear Magnetic Resonance (NMR) Spectrometer (1South)

Cite this