Selectivity of MHC-encoded peptide transporters from human, mouse and rat

Abstract

MAJOR histocompatibility complex (MHC) class I molecules present peptides from degraded intracellular antigens to CD8⁺ T cells¹. These peptides are translocated in an ATP-dependent fashion^2–4 into the lumen of the endoplasmic reticulum (ER) for binding to class I molecules^5,6 by means of the MHC-encoded transporters associated with antigen processing, TAP1 and TAP2. These are members of a family of proteins containing an ATP-binding cassette and form heterodimers in the ER membrane^7–10. Defects in the genes encoding TAP1 or TAP2 account for impaired class I assembly and antigen presentation in several human and rodent cell lines^7,11–13. Whereas MHC class I molecules select peptides according to binding motifs^14–17, it is not clear to what extent the TAP1–TAP2 transporters have peptide sequence and length specificity. Previous studies of the rat MHC class I molecule, RT1A^a, suggested a specific conveyance of peptides by rat TAP1–TAP2 (ref. 18). Here we substitute the amino- and carboxy-terminal and the penultimate amino-acid residues of model peptides to show that these residues influence the efficiency of transport. Human TAP and rat TAP^a translocated peptides with hydrophobic and basic C termini, whereas mouse TAP and rat TAP^u preferred peptides with hydrophobic C termini. This pattern correlates with the predominant peptide binding profiles of mouse and human class I molecules.