Proline substitution independently enhances H-2D(b) complex stabilization and TCR recognition of melanoma-associated peptides.
The immunogenicity of H-2D(b) (D(b)) restricted epitopes can be significantly increased by substituting peptide position 3 to a proline (p3P). The p3P modification enhances MHC stability without altering the conformation of the modified epitope allowing for T-cell cross-reactivity with the native peptide. The present study reveals how specific interactions between p3P and the highly conserved MHC heavy chain residue Y159 increase the stability of D(b) in complex with an optimized version of the melanoma-associated epitope gp10025-33 . Furthermore, the p3P modification directly increased the affinity of the D(b)/gp10025-33 -specific T-cell receptor (TCR) pMel. Surprisingly, the enhanced TCR binding was independent from the observed increased stability of the optimized D(b)/gp10025-33 complex and from the interactions formed between p3P and Y159, indicating a direct effect of the p3P modification on TCR recognition.
Science for Life Laboratory, Center for Infectious Medicine (CIM), Department of Medicine, Karolinska Insitutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Hannes
H
Uchtenhagen
Esam T
ET
Abualrous
Evi
E
Stahl
Eva B
EB
Allerbring
Marjolein
M
Sluijter
Martin
M
Zacharias
Tatyana
T
Sandalova
Thorbald
T
van Hall
Sebastian
S
Springer
Per-Åke
PÅ
Nygren
Adnane
A
Achour
D019943:Amino Acid Substitution; D000818:Animals; D018360:Crystallography, X-Ray; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D064532:Histocompatibility Antigen H-2D / Q000737:chemistry / Q000276:immunology* / Q000648:ultrastructure; D051379:Mice; D056004:Molecular Dynamics Simulation; D011392:Proline / Q000235:genetics / Q000276:immunology*; D011487:Protein Conformation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D020349:Surface Plasmon Resonance; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D058951:gp100 Melanoma Antigen / Q000235:genetics / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D064532:Histocompatibility Antigen H-2D; D011948:Receptors, Antigen, T-Cell; D058951:gp100 Melanoma Antigen; D011392:Proline
MHC; Structural Biology; T-cell epitope; TCR; Tumor antigen