The ABC of channel regulation

The ABC Transporter/Channel Superfamily The ATP-binding cassette (ABC) superfamily is probably the largest and most diverse family of proteins that mediate the selective movement of solutes across biological membranes. Many ABC proteins are of considerable clinical significance: human P-glycoprotein (P-gp) confers resistance of cancers to chemotherapeutic drugs, Pghl has a role in chloroquine resistance of the malarial parasite, SUR is the receptor for sulphonylureas used to treat diabetes and is mutated in patients with persistent hyperinsulinemic hypoglycemia of infancy, and genes encoding ABC transporters are mutated in inherited syndromes such as adrenoleukodystrophy, Zellweger syndrome, and cystic fibrosis. Thus, the molecular mechanisms by which ABC transporters operate, and their physiological roles, are of more than passing academic interest. Over 100 ABC transporters have been identified in species ranging from Escherichia coil to human (Higgins, 1992). Each is specific for a single substrate or group of related substrates that can range from inorganic ions to sugars and amino acids, complex polysaccharides and proteins. All ABC transporters share a common domain organization with four "core" domains that may be expressed as separate polypeptides or can be fused together into larger, multidomain proteins (Figure 1). Two transmembrane domains span the membrane multiple times to form the pathway through which solute crosses the membrane and determine the substrate specificity/selectivity of the transporter. Two ATP-binding domains, Iocated at the cytosolic face of the membrane, couple ATP hydrolysis to solute movement. These latter domains share 30%-40% sequence identity with the equivalent domains from other ABC transporters, irrespective of their substrate specificity or species of origin, readily distinguishing these ATP-binding cassettes from other nucleotidebinding proteins. Despite many elegant genetic and biochemical studies, we are still some way from understanding the molecular mechanisms by which ABC transporters mediate transmembrane translocation of solute. This is, principally, because of a lack of structural information. The vast majority of ABC proteins are active transporters, utilizing the energy of ATP hydrolysis to pump solute across the membrane. However, the finding that one apparently typical ABC transporter, the cystic fibrosis gene product CFTR (for cystic fibrosis transmembrane conductance regulator), is an ion channel has challenged conventional views on the distinction between channels and transporters. It is not known whether any other ABC proteins are channels rather than transporters. However, over the past year, it has emerged that several ABC proteins regulate heterologous channels, and perhaps other membrane proteins, besides possessing their own intrinsic transporter/channel activities.