The energetic basis underpinning T-cell receptor recognition of a super-bulged peptide bound to a major histocompatibility complex class I molecule

Yu Chih Liu, Zhenjun Chen, Scott R Burrows, Anthony W Purcell, James McCluskey, Jamie Rossjohn, Stephanie Gras

Research output: Contribution to journalArticleResearchpeer-review

21 Citations (Scopus)

Abstract

While the Major Histocompatibility Complex Class I (MHC-I) molecules typically bind short peptide (p) fragments (8-10 amino acids in length), longer, bulged, peptides are often be presented by MHC-I. Such bulged pMHC-I complexes represent challenges for T-cell receptor (TCR) ligation, although the general principles underscoring the interaction between TCRs and bulged pMHC-I complexes are unclear. To address this, we have explored the energetic basis of how an immunodominant TCR (termed SB27) binds to a 13 amino acid viral peptide (LPEPLPQGQLTAY) complexed to Human Leukocyte Antigen (HLA) B*3508. Using the crystal structure of the SB27 TCR-HLA B*3508LPEP complex as a guide, we undertook a comprehensive alanine-scanning mutagenesis approach at the TCR-pMHC-I interface and examined the effect of the mutations by biophysical (affinity measurements) and cellular approaches (tetramer staining). While the structural footprint on the HLA B*3508 was small, the energetic footprint was even smaller in that only two HLA B*3508 residues were critical for the TCR interaction. Instead, the energetic basis of this TCR-pMHC-I interaction was attributed to peptide-mediated interactions in which the complementarity determining region (CDR) 3alpha and germline encoded CDR1beta loops of the SB27 TCR played the principal role. Our findings highlight the peptide-centricity of TCR ligation towards a bulged pMHC-I complex.
Original languageEnglish
Pages (from-to)12267 - 12276
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number15
DOIs
Publication statusPublished - 2012

Cite this

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title = "The energetic basis underpinning T-cell receptor recognition of a super-bulged peptide bound to a major histocompatibility complex class I molecule",
abstract = "While the Major Histocompatibility Complex Class I (MHC-I) molecules typically bind short peptide (p) fragments (8-10 amino acids in length), longer, bulged, peptides are often be presented by MHC-I. Such bulged pMHC-I complexes represent challenges for T-cell receptor (TCR) ligation, although the general principles underscoring the interaction between TCRs and bulged pMHC-I complexes are unclear. To address this, we have explored the energetic basis of how an immunodominant TCR (termed SB27) binds to a 13 amino acid viral peptide (LPEPLPQGQLTAY) complexed to Human Leukocyte Antigen (HLA) B*3508. Using the crystal structure of the SB27 TCR-HLA B*3508LPEP complex as a guide, we undertook a comprehensive alanine-scanning mutagenesis approach at the TCR-pMHC-I interface and examined the effect of the mutations by biophysical (affinity measurements) and cellular approaches (tetramer staining). While the structural footprint on the HLA B*3508 was small, the energetic footprint was even smaller in that only two HLA B*3508 residues were critical for the TCR interaction. Instead, the energetic basis of this TCR-pMHC-I interaction was attributed to peptide-mediated interactions in which the complementarity determining region (CDR) 3alpha and germline encoded CDR1beta loops of the SB27 TCR played the principal role. Our findings highlight the peptide-centricity of TCR ligation towards a bulged pMHC-I complex.",
author = "Liu, {Yu Chih} and Zhenjun Chen and Burrows, {Scott R} and Purcell, {Anthony W} and James McCluskey and Jamie Rossjohn and Stephanie Gras",
year = "2012",
doi = "10.1074/jbc.M112.344689",
language = "English",
volume = "287",
pages = "12267 -- 12276",
journal = "Journal of Biological Chemistry",
issn = "1083-351X",
publisher = "American Society for Biochemistry and Molecular Biology",
number = "15",

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The energetic basis underpinning T-cell receptor recognition of a super-bulged peptide bound to a major histocompatibility complex class I molecule. / Liu, Yu Chih; Chen, Zhenjun; Burrows, Scott R; Purcell, Anthony W; McCluskey, James; Rossjohn, Jamie; Gras, Stephanie.

In: Journal of Biological Chemistry, Vol. 287, No. 15, 2012, p. 12267 - 12276.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - The energetic basis underpinning T-cell receptor recognition of a super-bulged peptide bound to a major histocompatibility complex class I molecule

AU - Liu, Yu Chih

AU - Chen, Zhenjun

AU - Burrows, Scott R

AU - Purcell, Anthony W

AU - McCluskey, James

AU - Rossjohn, Jamie

AU - Gras, Stephanie

PY - 2012

Y1 - 2012

N2 - While the Major Histocompatibility Complex Class I (MHC-I) molecules typically bind short peptide (p) fragments (8-10 amino acids in length), longer, bulged, peptides are often be presented by MHC-I. Such bulged pMHC-I complexes represent challenges for T-cell receptor (TCR) ligation, although the general principles underscoring the interaction between TCRs and bulged pMHC-I complexes are unclear. To address this, we have explored the energetic basis of how an immunodominant TCR (termed SB27) binds to a 13 amino acid viral peptide (LPEPLPQGQLTAY) complexed to Human Leukocyte Antigen (HLA) B*3508. Using the crystal structure of the SB27 TCR-HLA B*3508LPEP complex as a guide, we undertook a comprehensive alanine-scanning mutagenesis approach at the TCR-pMHC-I interface and examined the effect of the mutations by biophysical (affinity measurements) and cellular approaches (tetramer staining). While the structural footprint on the HLA B*3508 was small, the energetic footprint was even smaller in that only two HLA B*3508 residues were critical for the TCR interaction. Instead, the energetic basis of this TCR-pMHC-I interaction was attributed to peptide-mediated interactions in which the complementarity determining region (CDR) 3alpha and germline encoded CDR1beta loops of the SB27 TCR played the principal role. Our findings highlight the peptide-centricity of TCR ligation towards a bulged pMHC-I complex.

AB - While the Major Histocompatibility Complex Class I (MHC-I) molecules typically bind short peptide (p) fragments (8-10 amino acids in length), longer, bulged, peptides are often be presented by MHC-I. Such bulged pMHC-I complexes represent challenges for T-cell receptor (TCR) ligation, although the general principles underscoring the interaction between TCRs and bulged pMHC-I complexes are unclear. To address this, we have explored the energetic basis of how an immunodominant TCR (termed SB27) binds to a 13 amino acid viral peptide (LPEPLPQGQLTAY) complexed to Human Leukocyte Antigen (HLA) B*3508. Using the crystal structure of the SB27 TCR-HLA B*3508LPEP complex as a guide, we undertook a comprehensive alanine-scanning mutagenesis approach at the TCR-pMHC-I interface and examined the effect of the mutations by biophysical (affinity measurements) and cellular approaches (tetramer staining). While the structural footprint on the HLA B*3508 was small, the energetic footprint was even smaller in that only two HLA B*3508 residues were critical for the TCR interaction. Instead, the energetic basis of this TCR-pMHC-I interaction was attributed to peptide-mediated interactions in which the complementarity determining region (CDR) 3alpha and germline encoded CDR1beta loops of the SB27 TCR played the principal role. Our findings highlight the peptide-centricity of TCR ligation towards a bulged pMHC-I complex.

UR - http://www.jbc.org/content/287/15/12267.full.pdf

U2 - 10.1074/jbc.M112.344689

DO - 10.1074/jbc.M112.344689

M3 - Article

VL - 287

SP - 12267

EP - 12276

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 15

ER -