The principles of peptide selection by the transporter associated with antigen processing

The adaptive immune response eliminates infected and cancer cells through the recognition of antigenic peptides displayed by major compatibility complex class I (MHC-I) molecules[1][1], [2][2]. A single transporter, the transporter associated with antigen processing (TAP), supplies nearly the entire peptide repertoire for the many MHC-I alleles[3][3]–[5][4]. A fundamental unresolved question is how TAP transports peptides with vast sequence diversity. Here, using cryo-electron microscopy (cryo-EM), we determined seven structures of human TAP in the presence and absence of peptides with different sequences and lengths. We observe that peptides are suspended in the transmembrane cavity of TAP with the peptide N-and C-termini anchored at two distal binding pockets. The central residues of the peptide are unrestricted, making few contacts with TAP. A minimum of eight residues is required to bridge the two binding pockets, aligning with the lower length limit for MHC-I binding[6][5], [7][6]. Mutations in TAP that disrupt hydrogen bonds with the peptide termini nearly abolish MHC-I surface expression, indicating that binding depends on interactions with mainchain atoms at the two termini. By utilizing two spatially separated binding pockets and concentrating interactions at the two ends of the peptide, TAP functions as a molecular caliper, selecting peptides for length while permitting sequence diversity. ### Competing Interest Statement The authors have declared no competing interest. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-5 [5]: #ref-6 [6]: #ref-7