![]() Since many transporters are linked to human diseases, such as cystic fibrosis, Tangier disease, or Dubin-Johnson syndrome, elucidating the molecular mechanisms and functions of ABC transporters is of high interest 2, 3.Ī representative ABC exporter is the half-transporter associated with antigen processing-like (ABCB9, TAPL), which translocates peptides into the lumen of lysosomes 4. Consequently, half-transporters can either form homo- or heterodimers. In eukaryotes, the ABC transporters exist as full-transporters with all four domains combined in one polypeptide chain or as half-transporters composed of one TMD and one NBD. Their basic architecture comprises two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs). ABC transporters include importers, exporters, channels, and regulators. The substrate spectrum of ABC transporters ranges from small soluble molecules, hydrophobic drugs and lipids to large proteins 1. In conclusion, TAPL does not differentiate between transport substrates in the binding process but during the following steps in the transport cycle, whereas, on the other hand, not only the coupling efficiency but also the activation energy varies depending on the size of peptide substrate.ĪTP binding cassette (ABC) transporters are part of the ABC protein superfamily and form the largest class of primary active transport proteins, which couple ATP hydrolysis with substrate transport. While GTP is hydrolyzed as good as ATP, peptide transport is significantly reduced. ![]() Remarkably, also the type of nucleotide determines the uncoupling. Uncoupling between ATP hydrolysis and peptide transport increases with peptide length. TAPL shows a basal ATPase activity, which is inhibited in the presence of longer peptides. This difference can be attributed to a higher activation energy for the longer peptide. Although longer and shorter peptides bind with the same affinity and are transported with identical K m values, they differ significantly in their transport rates. Therefore, we analyzed the coupling of peptide binding, transport and ATP hydrolysis for different substrate sizes. Although the structure and the function of ABC transporters were intensively studied in the past, details about the single steps of the transport cycle are still elusive. ![]() TAPL forms a homodimeric transport complex, which translocates oligo- and polypeptides into the lumen of lysosomes driven by ATP hydrolysis. The lysosomal polypeptide transporter TAPL belongs to the superfamily of ATP-binding cassette transporters.
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