This project delivers a rich and cohesive narrative on the molecular foundations of antigen processing and presentation, with far-reaching implications for immunology, virology, and therapeutic development. The studies collectively detail how antigenic peptides are translocated, selected, and presented by MHC I molecules, and how this process is regulated, hijacked, or modulated.
Key findings include the full structural cycle of ATP-binding cassette (ABC) transporters involved in peptide translocation, revealing that ATP binding alone can drive conformational changes necessary for substrate movement. This insight revises longstanding models of ATP-coupled transport and highlights a unidirectional power stroke mechanism. In the context of the immune system, this mechanistic knowledge informs how the ABC transporter associated with antigen processing (TAP) fuels antigen import into the ER.
Parallel structural and functional studies on the peptide-loading complex (PLC) uncovered the critical role of chaperones like tapasin, TAPBPR, and ERp57 in stabilizing and editing MHC I-peptide interactions. Several publications resolved high-resolution structures of various PLC subcomplexes, elucidating how these components work in concert to ensure that only high-affinity peptides are presented at the cell surface. Importantly, the studies also demonstrated the dynamic interplay between peptide selection and N-linked glycan processing, tightly linking MHC I quality control to ER homeostasis.
Viral immune evasion was another focal point. Structural and functional studies showed how herpesviral proteins (e.g. ICP47 and US6) arrest the PLC in specific conformational states or block MHC I trafficking altogether. These mechanisms help viruses evade cytotoxic T cell detection. Tools such as semisynthetic, light-controllable inhibitors of the PLC were developed to probe and potentially exploit these evasion strategies therapeutically.
On the technological front, the use of synthetic biology platforms, cryo-EM, and super-resolution imaging enabled the precise visualization of molecular complexes and their spatiotemporal organization in living cells. These approaches also paved the way for quantitative measurements of peptide transport and editing, making it possible to dissect the energetic landscape of antigen processing with unprecedented precision.
The exploitation and dissemination of these results have been robust. Findings have laid a structural and mechanistic foundation for rational vaccine design and immunotherapies targeting cancer and infectious diseases. In particular, insights into TCR-peptide-MHC I interactions provide a molecular blueprint for developing T cell-based therapies. Several tools and methods, including macrocyclic peptide inhibitors and synthetic PLC regulators, are readily adaptable for academic and translational research.
Dissemination has occurred through high-impact publications in Nature, Cell, Nature Communications, eLife, and PNAS, as well as in key review articles in Annu Rev Biochem and Annu Rev Biophys that summarize and contextualize the findings for broader audiences in structural biology, immunology, and virology. Data and structural models have been made publicly available in repositories such as the Protein Data Bank (PDB) and Electron Microscopy Data Bank (EMDB), further enhancing accessibility and reuse. Additionally, insights from these works have been presented at major international conferences and integrated into educational and collaborative research networks, facilitating continued knowledge exchange across disciplines.
