Related Experiment Video
Updated: May 28, 2026
Generating De Novo Antigen-specific Human T Cell Receptors by Retroviral Transduction of Centric Hemichain
Published on: October 25, 2016
Structural basis for TCR recognition of a Rac1 neoantigen arising from anchor residue mutation
Yayun Zeng1, Dandan Yang1, Jianfeng Zhao2
1Laboratory of Structural Immunology, Hengyang Medical School, University of South China, Hengyang, Hunan, China; Department of Hepatopancreatobiliary Surgery, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China.
Abstract:
T cell receptor (TCR)-based immunotherapy can drive cancer regression by targeting neoantigens derived from mutations in self-proteins. Most neoantigens result from mutations in solvent-exposed residues creating neoepitopes that allow highly specific TCR recognition. Here, we describe a melanoma neoantigen (Rac1P29S) caused by a mutation at a primary anchor residue. Unlike typical cases, the immunogenicity of Rac1P29S stems from this anchor mutation, which permits MHC presentation of the mutant peptide but not the wild-type counterpart. We determined the structures of both the mutant Rac1P29S-HLA-A2 complex and its complex with the tumor-specific TCR 5934. These structures show how the P29S mutation makes a Rac1 self- peptide visible to T cells. Notably, TCR 5934 primarily engages the C-terminal, non-mutated P8 threonine residue of Rac1P29S -far from the N-terminal mutated P2 serine. This contrasts with most neoantigen-specific TCRs, which typically focus on the mutated residue to distinguish mutant from wild-type peptides. Together, these findings provide a structural framework to guide the development of TCR-based cancer immunotherapies.
Insights
This study reveals a unique melanoma neoantigen, Rac1P29S, where a mutation enables T cell receptor (TCR) recognition. The findings offer structural insights for developing novel TCR-based cancer immunotherapies.
Area of Science:
- Immunology
- Structural Biology
- Oncology
Background:
- T cell receptor (TCR)-based immunotherapy targets cancer neoantigens.
- Neoantigens typically arise from mutations in exposed residues for TCR recognition.
Purpose of the Study:
- To describe a novel melanoma neoantigen, Rac1P29S, and its interaction with a tumor-specific TCR.
- To elucidate the structural basis of TCR recognition for this unique neoantigen.
Main Methods:
- Determined the structures of the Rac1P29S-HLA-A2 complex.
- Determined the structure of the Rac1P29S-HLA-A2 complex bound to tumor-specific TCR 5934.
Main Results:
- The Rac1P29S mutation at an anchor residue allows MHC presentation of the mutant peptide.
- TCR 5934 recognizes the Rac1P29S peptide by engaging a non-mutated C-terminal residue, distinct from typical TCR binding.
- Structural analysis revealed how the P29S mutation renders the Rac1 self-peptide detectable by T cells.
Conclusions:
- The Rac1P29S neoantigen's immunogenicity is driven by an anchor mutation, enabling MHC presentation.
- TCR 5934's recognition mechanism provides a novel paradigm, differing from TCRs that target mutated residues.
- These structural insights can guide the design of advanced TCR-based cancer immunotherapies.
More Related Videos
Related Concept Videos
01:28Diversity of Antigen Receptors
Before encountering any antigen, lymphocytes express these receptors. On B cells, the antigen receptor is a membrane-bound antibody molecule called BCR; on T cells, it is a T cell receptor or TCR. B and T cell receptors are composed of two...
01:22T Cell Activation and Clonal Selection
Naive T cells that have not yet encountered an antigen express two primary CD...
01:00Enzyme-linked Receptors
Neurotrophin (NT) receptors are a family of RTKs, including trkA, trkB, and trkC (tropomyosin-related kinase) receptors. TrkA is specific for nerve growth factor (NGF), neurotrophin-6, and neurotrophin-7. TrkB binds...
02:38The Ras Gene
Ras is a superfamily...
01:26Receptor Tyrosine Kinases
01:45Tail-anchoring of Proteins in the ER Membrane