Mechanistic determinants of the directionality and energetics of active export by a heterodimeric ABC transporter.

The ATP-binding cassette (ABC) transporter associated with antigen processing (TAP) participates in immune surveillance by moving proteasomal products into the endoplasmic reticulum (ER) lumen for major histocompatibility complex class I loading and cell surface presentation to cytotoxic T cells. Here we delineate the mechanistic basis for antigen translocation. Notably, TAP works as a molecular diode, translocating peptide substrates against the gradient in a strict unidirectional way.

The MHC I loading complex: a multitasking machinery in adaptive immunity.

Recognition and elimination of virally or malignantly transformed cells are pivotal tasks of the adaptive immune system. For efficient immune detection, snapshots of the cellular proteome are presented as epitopes on major histocompatibility complex class I (MHC I) molecules for recognition by cytotoxic T cells. Knowledge about the track from the equivocal protein to the presentation of antigenic peptides has greatly expanded, leading to an astonishingly elaborate understanding of the MHC I peptide loading pathway.

Molecular architecture of the MHC I peptide-loading complex: one tapasin molecule is essential and sufficient for antigen processing.

The loading of antigen-derived peptides onto MHC class I molecules for presentation to cytotoxic T cells is a key process in adaptive immune defense. Loading of MHC I is achieved by a sophisticated machinery, the peptide-loading complex (PLC), which is organized around the transporter associated with antigen processing (TAP) with the help of several auxiliary proteins. As an essential adapter protein recruiting MHC I molecules to TAP, tapasin catalyzes peptide loading of MHC I.

Direct evidence that the N-terminal extensions of the TAP complex act as autonomous interaction scaffolds for the assembly of the MHC I peptide-loading complex.

The loading of antigenic peptides onto major histocompatibility complex class I (MHC I) molecules is an essential step in the adaptive immune response against virally or malignantly transformed cells. The ER-resident peptide-loading complex (PLC) consists of the transporter associated with antigen processing (TAP1 and TAP2), assembled with the auxiliary factors tapasin and MHC I. Here, we demonstrated that the N-terminal extension of each TAP subunit represents an autonomous domain, named TMD(0), which is correctly targeted to and inserted into the ER membrane.