Sulphonylurea receptor <p>ABC transporters belong to the ATP-Binding Cassette (ABC) superfamily, which uses the hydrolysis of ATP to energise diverse biological systems. ABC transporters minimally consist of two conserved regions: a highly conserved ATP binding cassette (ABC) and a less conserved transmembrane domain (TMD). These can be found on the same protein or on two different ones. Most ABC transporters function as a dimer and therefore are constituted of four domains, two ABC modules and two TMDs.</p> <p>ABC transporters are involved in the export or import of a wide variety of substrates ranging from small ions to macromolecules. The major function of ABC import systems is to provide essential nutrients to bacteria. They are found only in prokaryotes and their four constitutive domains are usually encoded by independent polypeptides (two ABC proteins and two TMD proteins). Prokaryotic importers require additional extracytoplasmic binding proteins (one or more per systems) for function. In contrast, export systems are involved in the extrusion of noxious substances, the export of extracellular toxins and the targeting of membrane components. They are found in all living organisms and in general the TMD is fused to the ABC module in a variety of combinations. Some eukaryotic exporters encode the four domains on the same polypeptide chain [<cite idref="PUB00014769"/>].</p> <p>The ABC module (approximately two hundred amino acid residues) is known to bind and hydrolyse ATP, thereby coupling transport to ATP hydrolysis in a large number of biological processes. The cassette is duplicated in several subfamilies. Its primary sequence is highly conserved, displaying a typical phosphate-binding loop: Walker A, and a magnesium binding site: Walker B. Besides these two regions, three other conserved motifs are present in the ABC cassette: the switch region which contains a histidine loop, postulated to polarise the attaching water molecule for hydrolysis, the signature conserved motif (LSGGQ) specific to the ABC transporter, and the Q-motif (between Walker A and the signature), which interacts with the gamma phosphate through a water bond. The Walker A, Walker B, Q-loop and switch region form the nucleotide binding site [<cite idref="PUB00017894"/>, <cite idref="PUB00017895"/>, <cite idref="PUB00017896"/>].</p> <p>The 3D structure of a monomeric ABC module adopts a stubby L-shape with two distinct arms. ArmI (mainly beta-strand) contains Walker A and Walker B. The important residues for ATP hydrolysis and/or binding are located in the P-loop. The ATP-binding pocket is located at the extremity of armI. The perpendicular armII contains mostly the alpha helical subdomain with the signature motif. It only seems to be required for structural integrity of the ABC module. ArmII is in direct contact with the TMD. The hinge between armI and armII contains both the histidine loop and the Q-loop, making contact with the gamma phosphate of the ATP molecule. ATP hydrolysis leads to a conformational change that could facilitate ADP release. In the dimer the two ABC cassettes contact each other through hydrophobic interactions at the antiparallel beta-sheet of armI by a two-fold axis [<cite idref="PUB00017897"/>, <cite idref="PUB00017898"/>, <cite idref="PUB00017899"/>, <cite idref="PUB00004290"/>, <cite idref="PUB00025109"/>, <cite idref="PUB00026406"/>].</p> <p>The ATP-Binding Cassette (ABC) superfamily forms one of the largest of all protein families with a diversity of physiological functions [<cite idref="PUB00014769"/>]. Several studies have shown that there is a correlation between the functional characterisation and the phylogenetic classification of the ABC cassette [<cite idref="PUB00014769"/>, <cite idref="PUB00043654"/>]. More than 50 subfamilies have been described based on a phylogenetic and functional classification [<cite idref="PUB00014769"/>, <cite idref="PUB00017894"/>, <cite idref="PUB00043654"/>]; (for further information see http://www.tcdb.org/tcdb/index.php?tc=3.A.1).</p><p>The sulphonylurea receptor (SUR) is a member of the ATP-binding cassettesuperfamily that associates with certain K⁺ channel inward rectifiersubunits to form ATP-sensitive K⁺ channels (KATP channels) [<cite idref="PUB00005203"/>, <cite idref="PUB00005208"/>].These are a family of K⁺ channels that are inhibited by intracellular ATP, which cancouple metabolic state to cell excitability. Their presence on pancreaticislet beta cells allows the cells to function as metabolic sensors,regulating insulin release in relation to glucose metabolism. Furthermore,SUR is the site of action for the sulphonylurea oral hypoglycaemic agentsthat are used widely for the treatment of non-insulin dependent diabetesmellitus. When these agents bind to the sulphonlyurea receptor, they reduceKATP channel activity, stimulating insulin release.</p><p>As mentioned, SUR is a member of the ATP-binding cassette superfamily. This raises the possibilitythat SUR may transport some endogenous substance, as yet unidentified.Two closely related genes have been found to encode the sulphonylureareceptors, SUR1 and SUR2, there being three splice variants of the secondform [<cite idref="PUB00005551"/>]. They are thought to contain 13-17 transmembrane (TM) domains,with two potential nucleotide binding folds, and a large number of possibleprotein kinase A, or C phosphorylation sites. Comparison of the propertiesof cloned and wild-type KATP channels suggests that SUR1 may associate withthe inward rectifier subunit Kir6.2 to form the pancreatic beta cell KATPchannel. Splice variants of SUR2 (termed SUR2A and SUR2B) may form thecardiac and smooth muscle isoforms, respectively, again when combined withKir 6.2. This co-assembly likely occurs with an obligate 4:4 stoichiometry,giving rise to an octameric channel.</p><p>Mutations in SUR genes have been characterised; these can result intruncations of the second predicted nucleotide binding fold, leading topersistent hyperinsulinemic hypoglycaemia of infancy, a rare familialdisorder characterised by excessive, unregulated insulin secretion.</p>