Adenylate Kinase Activity in ABC Transporters

ABC transporters are remarkably versatile machines that move a wide array of substances, including both hydrophilic and hydrophobic molecules across membranes (1-4). They are constructed with a modular design; each transporter has two nucleotidebinding domains (NBDs) and two membrane-spanning domains (often comprising six transmembrane helices). The NBDs are highly conserved modules that interact with ATP to control transport. The membrane-spanning domains show little sequence conservation, consistent with highly divergent functions within the ABC transporter family. In some cases, additional modules (solute-binding and/or regulatory domains) participate in the ABC transporter complex to regulate function. The design and adaptability of ABC transporters have apparently served life well throughout evolution, because they form one of the largest families of proteins in eubacteria, archaea and eukarya. Not surprisingly, loss of ABC transporter function is implicated in many diseases, and they are therefore important targets for therapeutics (5). Some ABC transporters are pumps; their NBDs function as ATPases (Mg⋅ATP + H2O → Mg⋅ADP + Pi) and they spend the energy of ATP hydrolysis to move substances across a membrane against a gradient (6-8). However, the mechanisms coupling enzymatic activity to substrate transfer remain controversial, and the stoichiometry of transport the relationship between the number of ATP molecules hydrolyzed and the number of substrate molecules transported remains uncertain (1).