Nucleotide-dependent conformational changes direct peptide export by the transporter associated with antigen processing.
| Publication Type | Academic Article |
| Authors | Lee J, Manon V, Chen J |
| Journal | Immunity |
| Volume | 58 |
| Issue | 9 |
| Pagination | 2166-2175.e4 |
| Date Published | 08/29/2025 |
| ISSN | 1097-4180 |
| Keywords | Antigen Presentation, ATP-Binding Cassette Transporters, Adenosine Triphosphate |
| Abstract | The transporter associated with antigen processing (TAP) delivers peptide antigens from the cytoplasm into the endoplasmic reticulum (ER) for loading onto major histocompatibility complex class I (MHC-I) molecules. To examine the mechanisms of peptide transport and release into the ER, we determined cryo-electron microscopy structures of the human TAP heterodimer in multiple functional states along the transport cycle. In the inward-facing conformation, when the peptide translocation cavity within the TAP heterodimer is exposed to the cytosol, ATP binding strengthened intradomain assembly. Transition to the outward-facing conformation, when the transporter opens to the ER lumen, led to a complete reconfiguration of the peptide-binding site, facilitating peptide release. ATP hydrolysis opened the catalytically active nucleotide-binding consensus site, and the subsequent separation of the nucleotide-binding domains reset the transport cycle. These findings establish a comprehensive structural framework for understanding unilateral peptide transport, vanadate trapping, and trans-inhibition-an internal feedback mechanism that prevents excessive peptide accumulation and activation of the ER stress response. |
| DOI | 10.1016/j.immuni.2025.08.003 |
| PubMed ID | 40885191 |
| PubMed Central ID | PMC12422388 |