ABC transporters: the power to change

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Abstract
ATP-binding cassette (ABC) transporters constitute a ubiquitous superfamily of integral membrane proteins that are responsible for the ATP-powered translocation of many substrates across membranes. ABC transporters have a characteristic architecture that consists minimally of four domains: two ABC domains (or nucleotide-binding domains) with highly conserved sequence motifs and two transmembrane domains (TMDs). Additional domains can be fused to these core elements to confer regulatory functions, and a periplasmic binding protein is required for ligand delivery to prokaryotic importer members of this family. Similarities in the structure of the ABC domains structure support a common mechanism by which ABC transporters, both importers and exporters, orchestrate a series of nucleotide- and substrate-dependent conformational changes that result in substrate translocation across the membrane through an 'alternating-access'-type model. As ABC domains are also integrated into non-transport systems, including proteins that are involved in DNA repair and chromosome maintenance, it is likely that a common set of ATP-dependent conformational changes are relevant to all of these processes. The conformation of ABC transporters that is catalytically competent for nucleotide hydrolysis involves the binding of an ATP molecule between conserved sequence motifs at the interface between the two ABC domains. As a transporter cycles through the different stages of nucleotide binding and hydrolysis, the interface between the two ABC domains switches from the closed state, which is characteristic of ATP binding, to a more open conformation, which is associated with non-ATP states. TMDs are structurally heterogeneous, and three distinct sets of folds have been recognized. Although the detailed folds vary, they all interact with the helical domains of the ABCs through 'coupling helices', which are located in the loops between membrane-spanning helices. These interactions connect the conformations of the TMDs to the nucleotide state of the ABC domains. The activity of ABC transporters can be regulated at the level of protein function through the actions of domains that are fused to the ABCs and/or TMDs. Recent structural studies have established that trans-inhibition, in which the uptake of an extracellular substrate is inhibited by increasing intracellular concentrations of that species, can involve ligand binding to the carboxy-terminal domains of the ABCs that sterically separate these domains and prevent their association, which is required for ATP hydrolysis. Although idealized kinetic models can be described that qualitatively highlight aspects of the transport mechanism, an important goal is to develop quantitative models that detail the kinetic and molecular mechanisms by which ABC transporters couple the binding and hydrolysis of ATP to substrate translocation.

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