5mzm
Structure of H-2Db in complex with TEIPP APL Trh4 p3PStructure of H-2Db in complex with TEIPP APL Trh4 p3P
Structural highlights
FunctionCERS5_MOUSE Dihydroceramide synthase. Catalyzes the acylation of sphingosine to form dihydroceramide, with high selectivity toward palmitoyl-CoA as acyl donor compared to stearoyl-CoA. Inhibited by fumonisin B1.[1] [2] Publication Abstract from PubMedHuman cancers frequently display defects in Ag processing and presentation allowing for immune evasion, and they therefore constitute a significant challenge for T cell-based immunotherapy. We have previously demonstrated that the antigenicity of tumor-associated Ags can be significantly enhanced through unconventional residue modifications as a novel tool for MHC class I (MHC-I)-based immunotherapy approaches. We have also previously identified a novel category of cancer neo-epitopes, that is, T cell epitopes associated with impaired peptide processing (TEIPP), that are selectively presented by MHC-I on cells lacking the peptide transporter TAP. In this study, we demonstrate that substitution of the nonanchoring position 3 into a proline residue of the first identified TEIPP peptide, the murine Trh4, results in significantly enhanced recognition by antitumor CTLs toward the wild-type epitope. Although higher immunogenicity has in most cases been associated with increased MHC/peptide complex stability, our results demonstrate that the overall stability of H-2D(b) in complex with the highly immunogenic altered peptide ligand Trh4-p3P is significantly reduced compared with wild-type H-2D(b)/Trh4. Comparison of the crystal structures of the H-2D(b)/Trh4-p3P and H-2D(b)/Trh4 complexes revealed that the conformation of the nonconventional methionine anchor residue p5M is altered, deleting its capacity to form adequate sulfur-pi interactions with H-2D(b) residues, thus reducing the overall longevity of the complex. Collectively, our results indicate that vaccination with Thr4-p3P significantly enhances T cell recognition of targets presenting the wild-type TEIPP epitope and that higher immunogenicity is not necessarily directly related to MHC/peptide complex stability, opening for the possibility to design novel peptide vaccines with reduced MHC/peptide complex stability. The Immunogenicity of a Proline-Substituted Altered Peptide Ligand toward the Cancer-Associated TEIPP Neoepitope Trh4 Is Unrelated to Complex Stability.,Hafstrand I, Doorduijn EM, Sun R, Talyzina A, Sluijter M, Pellegrino S, Sandalova T, Duru AD, van Hall T, Achour A J Immunol. 2018 Mar 5. pii: jimmunol.1700228. doi: 10.4049/jimmunol.1700228. PMID:29507106[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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