Architectural principles of transporter-chaperone coupling within the native MHC I peptide-loading complex

Adaptive immunity depends on major histocompatibility complex class I (MHC I) presentation of peptides, a process orchestrated by the peptide-loading complex (PLC) in the endoplasmic reticulum. The PLC ensures precise peptide selection and loading and is a major target of viral immune evasion, notably by human cytomegalovirus (HCMV). Here, we report the 2.59–2.88 Å cryo-electron microscopy structure of native human PLC bound to the HCMV immune evasin US6. US6 inhibits the TAP1/2 transporter by laterally attaching its transmembrane helix to TAP2 using a disulfide-rich domain to mimic a translocating peptide. This domain blocks the ER-lumenal exit and locks TAP in an outward-facing conformation with closed nucleotide-binding domains and asymmetric ATP/ADP occlusion. The structure also reveals how TAP’s N-terminal transmembrane domains scaffold the MHC I chaperone tapasin. These findings elucidate the mechanism of US6-mediated immune evasion and highlight potential targets for therapeutic modulation of immune presentation in infection and cancer.