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Molecular Mechanism of ABC Exporters

        ATP-binding cassette (ABC) proteins belong to one of the largest superfamilies, which expands from prokaryotes to man. Most   ABC proteins are integral membrane ATPases that transport a wide variety of substrates across membranes. High-resolution structural information on full-length ABC proteins is very limited, and predominantly of bacterial importers that are very different from exporters. In addition, crystal structures of membrane proteins in detergent are static representations of proteins outside their native bilayer environment, and biochemical and biophysical studies are required to validate the structures and to elucidate the mechanisms of their function.

General domain structure of ABC proteins. A. The basic core structure is shown in yellow. TMD: transmembrane domain; NBD: nucleotide-binding domain. B. Different polypeptide arrangements forming the basic core domain of ABC proteins are illustrated. Separate polypeptides are depicted in different colors.

        The various functions of ABC proteins (e.g., ion channels, lipid transporters, drug transporters) depend on the divergent transmembrane domains, whereas nucleotide binding and hydrolysis, common to all ABC proteins, require the conserved NBDs. ABC transporters have a central translocation pathway accessible to only one side of the membrane at a time (alternate accessibility model), where the accessibility is controlled by the NBDs, the motor domains of ABC proteins. In the ATP-bound state, two ATP molecules are sandwiched between the NBDs, and it has been proposed that nucleotide-binding with the resulting NBD dimerization constitute the power stroke associated with active transport. ATP hydrolysis is required to dissociate the dimer by electrostatic repulsion between the products of ATP hydrolysis (ADP and Pi). The crystal structure of the lipid transporter MsbA supports this view, but that of the S. aureus ABC exporter Sav1866 challenges it. The latter supports the notion that structural constraints limit the magnitude of the conformational changes (i.e., the power stroke triggered by ATP binding consists of only moderate rearrangements that originate at the interface between the NBDs and propagate to the TMDs).

        Our general goal is to elucidate at the molecular level the conformational changes in ABC proteins during the transport cycle. In particular, we are working on defining the domain movements in P-glycoprotein and Sav1866 during the transport cycle. These studies will allow us to discriminate between the different proposed molecular models (e.g., large vs. small NBD movements).

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