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TitleArchitectural principles of transporter-chaperone coupling within the native MHC I peptide-loading complex.
Journal, issue, pagesSci Adv, Vol. 12, Issue 1, Page eaea7735, Year 2026
Publish dateJan 2, 2026
AuthorsMilena Stolz / Lukas Sušac / Amin Fahim / Rieke Keller / Lisa Saggau / Filippo Mancia / Simon Trowitzsch / Robert Tampé /
PubMed AbstractAdaptive 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 (ER). ...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 (ER). 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- to 2.88-Å cryo-electron microscopy structure of native human PLC bound to the HCMV immune evasin US6. US6 inhibits the transporter associated with antigen processing 1/2 (TAP1/2) 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 adenosine 5'-triphosphate/adenosine 5'-diphosphate occlusion. The structure also reveals how TAP's amino-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.
External linksSci Adv / PubMed:41481733 / PubMed Central
MethodsEM (single particle)
Resolution2.7 Å
Structure data

53923

9rcv

EMDB-53923, PDB-9rcv:
Structure of the Human Peptide-Loading Complex Arrested by HCMV US6
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsIMMUNE SYSTEM / antigen processing / adaptive immunity / cryo-EM / ER chaperones / MHC class I / transporter associated with antigen processing

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