The homodimeric ATP-binding cassette (ABC) transport complex TAPL (transporter associated with antigen processing-like, ABCB9) translocates a broad spectrum of peptides from the cytosol into the lumen of lysosomes. The presence of an extra N-terminal transmembrane domain (TMD0) lacking any sequence homology to known proteins distinguishes TAPL from most other ABC transporters of its subfamily. By dissecting TAPL, we could assign distinct functions to the core complex and TMD0. The core-TAPL complex, composed of six predicted transmembrane helices and a nucleotidebinding domain, is sufficient for peptide transport, showing that the core transport complex is correctly targeted to and assembled in the membrane. Strikingly, in contrast to the full-length transporter, the core translocation complex is targeted preferentially to the plasma membrane. However, TMD0 alone, comprising a putative four transmembrane helix bundle, traffics to lysosomes. Upon coexpression, TMD0 forms a stable non-covalently linked complex with the core translocation machinery and guides core-TAPL into lysosomal compartments. Therefore, TMD0 represents a unique domain, which folds independently and encodes the information for lysosomal targeting. These outcomes are discussed in respect of trafficking, folding and function of TAPL.

The transporter associated with antigen processing-like (TAPL) is a polypeptide transporter translocating cytosolic peptides into the lumen of lysosomes driven by ATP hydrolysis. TAPL belongs to the family of ABC transporters and forms a homodimer. This ABC transporter not only shows a broad tissue but also a wide phylogenetic distribution, because orthologs are still found in nematodes and insects. Here, we present the topology, substrate specificity, and distribution of this intracellular polypeptide transporter. Additionally, we will discuss its proposed physiological functions such as housekeeping together with a specialized factor for metabolite storage as well as for the adaptive immunity.