Stephanie van Hoppe

11 Introduction A B C T R AN S P O R T E R S Transport proteins play a central role in this thesis. Especially the ATP-binding cassette (ABC) transporters, which form a superfamily of active multi-spanning transmembrane efflux proteins. They make up one of the largest protein families and are highly preserved across living organisms of all kingdoms, from bacteria to humans, indicating their essential functions. ABC transporters utilize energy derived from ATP hydrolysis in order to translocate specific substrates or regulate the activity of membrane channels. ATP hydrolysis is mediated in the majority of ABC transporters by two nucleotide-binding domains (NBDs), which interact with two transmembrane domains (TMDs). The NBDs bind and hydrolyze ATP, while the TMDs recognize and bind a specific substrate to translocate it across the membrane, driven by conformational changes in the NBDs upon ATP binding and hydrolysis (1). This process is rendered schematically and simplified in Figure 1. Figure 1 - Schematic and simplified representation of the transport mechanism of ABC efflux proteins. NBDs bind ATP, whileTMDs recognize and bind the transport substrate. ATP is hydrolyzed to ADP and a phosphate group, whereby the conformation of the protein changes and the substrate is transported across the cell membrane to the extracellular matrix. There are 48 known human ABC transporters, which are classified into 6 subfamilies (ABCA, ABCB, ABCC, ABCD, ABCE/ABCF and ABCG). They transport endogenous and exogenous molecules and regulate cell integrity, metabolism and homeostasis, and are involved in a large number of processes that play a role in various human diseases, such T M D T M D Substrate NBD NBD T M D T M D T M D T M D T MD T MD NBD NBD NBD NBD NBD NBD ATP ATP ADP P1 ADP P1 T M D T M D NBD NBD Extracellular matrix Cytoplasm Figure 1 : Schematic and simplified representation of the transport mechanism of ABC efflux proteins. NBDs bind ATP, while TMDs recognize and bind the transport substrate. ATP is hydrolyzed to ADP and a phosphate group, whereby the conformation of the protein changes and the substrate is transported across the cell membrane to the extracellular matrix.