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

Area of Science:

• Structural Biology
• Immunology
• Virology

Background:

• Adaptive immunity relies on Major Histocompatibility Complex class I (MHC I) for peptide presentation, a process critical for immune surveillance.
• The peptide-loading complex (PLC) in the endoplasmic reticulum (ER) is essential for selecting and loading peptides onto MHC I.
• Viral immune evasion strategies, such as those employed by human cytomegalovirus (HCMV), often target the PLC to subvert immune responses.

Purpose of the Study:

• To determine the high-resolution cryo-electron microscopy structure of the native human PLC bound to the HCMV immune evasion protein US6.
• To elucidate the molecular mechanism by which US6 inhibits the transporter associated with antigen processing 1/2 (TAP1/2).
• To understand how TAP1/2 interacts with MHC I chaperones, specifically tapasin.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to obtain the structure of the native human PLC complexed with US6 at resolutions of 2.59–2.88 Å.
• Structural analysis focused on the interaction between US6 and TAP1/2, including the role of US6's disulfide-rich domain and transmembrane helix.
• Examination of the conformational state of TAP1/2, including its nucleotide-binding domains and interaction with tapasin.

Main Results:

• The structure reveals that US6 inhibits TAP1/2 by laterally associating its transmembrane helix with TAP2, mimicking a translocating peptide.
• US6's disulfide-rich domain blocks the ER-lumenal exit of TAP1/2 and locks it in an outward-facing conformation with closed nucleotide-binding domains.
• The structure elucidates how TAP's N-terminal transmembrane domains serve as a scaffold for the MHC I chaperone tapasin.

Conclusions:

• The findings provide a detailed molecular mechanism for US6-mediated immune evasion by HCMV, highlighting how viral proteins disrupt antigen presentation.
• The study reveals the structural basis for TAP1/2 inhibition and its interaction with tapasin, crucial for MHC I assembly.
• The identified structural features of the PLC and US6 interaction present potential therapeutic targets for modulating immune presentation in infectious diseases and cancer.