Principles of peptide selection by the transporter associated with antigen processing

Area of Science:

• Immunology
• Structural Biology
• Molecular Biology

Background:

• The immune system relies on major histocompatibility complex class I (MHC-I) molecules to present antigens from diseased cells.
• The transporter associated with antigen processing (TAP) is essential for delivering antigenic peptides into the endoplasmic reticulum for MHC-I loading.

Purpose of the Study:

• To elucidate the mechanism by which TAP selects peptides for MHC-I presentation.
• To understand the structural basis of peptide specificity in TAP.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine structures of human TAP.
• Structures were captured in the presence and absence of peptides with varying sequences and lengths.
• Mutational analysis was performed to assess the role of peptide-binding interactions.

Main Results:

• TAP binds peptides of 8-9 residues in an extended conformation, irrespective of sequence.
• Two peptide-anchoring pockets engage the N- and C-termini of peptides, acting as a molecular caliper.
• Peptide binding induces conformational changes in TAP, priming it for ATP hydrolysis.
• Mutations disrupting N- and C-terminal hydrogen bonds significantly impair MHC-I surface expression.

Conclusions:

• TAP selects peptides primarily based on length, not sequence, ensuring broad antigen diversity for MHC-I presentation.
• This length-based selection mechanism is critical for effective immune surveillance and pathogen defense.