Small but important – various functions of the N-terminal domain TMD0

The ABC transporter TAPL translocates polypeptides with a broad length distribution from the cytosol into the lysosomal lumen driven by ATP hydrolysis. The length of the transported peptides ranges from 6- up to at least 59-mers, as long as they are unfolded and have free termini. TAPL is expressed in various tissues like testes, spinal cord and brain. Additionally, its expression is strongly induced in dendritic cells and macrophages, suggesting a role in the adaptive immunity. TAPL is a half-transporter and forms a homodimeric complex. Each subunit consists of an N-terminal transmembrane (TMD) and a C-terminal nucleotide binding domain (NBD). The TMD can be further subdivided into the N-terminal TMD0, which shows no sequence homology to any protein in the databases, and the C-terminal six TM helices which form together with the NBDs core-TAPL. The core complex is able to dimerize and is fully active in peptide transport. However, the truncated transporter is mislocalized to the plasma membrane and does not interact anymore with LAMP-1 und -2. Therefore, TMD0 takes over a dual function in subcellular targeting and mediating protein interaction. As shown with LAMP-1/2 deficient cells, the interaction with these proteins has no impact on transport activity or subcellular localization, but it drastically reduces the stability of TAPL.