Conversion of a T cell antagonist into an agonist by repairing a defect in the TCR/peptide/MHC interface: implications for TCR signaling.
The structure of the A6 alphabetaTCR/HTLV-1 Tax-peptide/MHC I complex with proline 6 of Tax substituted with alanine (P6A), an antagonist, is nearly identical to the structure with wild-type Tax agonist. Neither the proline in the agonist nor the alanine in the antagonist is contacted by the alphabetaTCR. Here, we demonstrate that antagonist activity of P6A is associated with low affinity of the A6 alphabetaTCR for Tax-P6A/HLA-A2. We show that stepwise repair of a packing defect in the TCR/MHC interface using N-alkylated amino acids results in stepwise increases in TCR affinity and activity. Kinetic and thermodynamic measurements suggest that for some ligands the range of T cell outcomes does not correlate with either their alphabetaTCR affinity or the half-life of the alphabetaTCR/peptide/MHC complex.
Baker
B M
BM
Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.
Gagnon
S J
SJ
Biddison
W E
WE
Wiley
D C
DC
D000409:Alanine / Q000378:metabolism; D019943:Amino Acid Substitution / Q000276:immunology*; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D003601:Cytotoxicity Tests, Immunologic; D016356:Gene Products, tax / Q000737:chemistry / Q000378:metabolism; D005998:Glycine / Q000378:metabolism; D015789:HLA-A2 Antigen / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011392:Proline / Q000378:metabolism; D011485:Protein Binding / Q000276:immunology; D017510:Protein Folding; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D012521:Sarcosine / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D013816:Thermodynamics; D014461:Ultracentrifugation / Q000379:methods; D014867:Water
D016356:Gene Products, tax; D015789:HLA-A2 Antigen; D008024:Ligands; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D014867:Water; D011392:Proline; D000409:Alanine; D005998:Glycine; D012521:Sarcosine