title: CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations.
abstract: CBS domains are defined as sequence motifs that occur in several different proteins in all kingdoms of life. Although thought to be regulatory, their exact functions have been unknown. However, their importance was underlined by findings that mutations in conserved residues within them cause a variety of human hereditary diseases, including (with the gene mutated in parentheses): Wolff-Parkinson-White syndrome (gamma 2 subunit of AMP-activated protein kinase); retinitis pigmentosa (IMP dehydrogenase-1); congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members); and homocystinuria (cystathionine beta-synthase). AMP-activated protein kinase is a sensor of cellular energy status that is activated by AMP and inhibited by ATP, but the location of the regulatory nucleotide-binding sites (which are prime targets for drugs to treat obesity and diabetes) was not characterized. We now show that tandem pairs of CBS domains from AMP-activated protein kinase, IMP dehydrogenase-2, the chloride channel CLC2, and cystathionine beta-synthase bind AMP, ATP, or S-adenosyl methionine,while mutations that cause hereditary diseases impair this binding. This shows that tandem pairs of CBS domains act, in most cases, as sensors of cellular energy status and, as such, represent a newly identified class of binding domain for adenosine derivatives.
authors.affiliation: Division of Molecular Physiology, Faculty of Life Sciences, Wellcome Trust Biocentre, University of Dundee, Scotland, United Kingdom.
authors.forename: John W
authors.initials: JW
authors.lastname: Scott
authors.forename: Simon A
authors.initials: SA
authors.lastname: Hawley
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Green
authors.forename: Miliea
authors.initials: M
authors.lastname: Anis
authors.forename: Greg
authors.initials: G
authors.lastname: Stewart
authors.forename: Gillian A
authors.initials: GA
authors.lastname: Scullion
authors.forename: David G
authors.initials: DG
authors.lastname: Norman
authors.forename: D Grahame
authors.initials: DG
authors.lastname: Hardie
mesh_terms: D000241:Adenosine / Q000737:chemistry*; D000249:Adenosine Monophosphate / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000495:Allosteric Site; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008099:Liver / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D012174:Retinitis Pigmentosa / Q000473:pathology
chemical_list: D018076:DNA, Complementary; D008024:Ligands; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D004247:DNA; D005982:Glutathione Transferase; D000241:Adenosine