CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations

John W. Scott, Simon A. Hawley, Kevin A. Green, Miliea Anis, Greg Stewart, Gillian A. Scullion, David G. Norman, D. Grahame Hardie

    Research output: Contribution to journalArticle

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    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 (?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 ß-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 ß-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.
    Original languageEnglish
    Pages (from-to)274-284
    Number of pages11
    JournalJournal of Clinical Investigation
    Volume113
    Issue number2
    DOIs
    Publication statusPublished - 2004

    Fingerprint

    AMP-Activated Protein Kinases
    IMP Dehydrogenase
    Cystathionine
    Adenosine
    Inborn Genetic Diseases
    Chloride Channels
    Adenosine Monophosphate
    Ligands
    Mutation
    Adenosine Triphosphate
    Myotonia Congenita
    Homocystinuria
    Nephrolithiasis
    Wolff-Parkinson-White Syndrome
    Retinitis Pigmentosa
    Methionine
    Nucleotides
    Obesity
    Binding Sites
    Pharmaceutical Preparations

    Keywords

    • CBS domains

    Cite this

    Scott, John W. ; Hawley, Simon A. ; Green, Kevin A. ; Anis, Miliea ; Stewart, Greg ; Scullion, Gillian A. ; Norman, David G. ; Hardie, D. Grahame. / CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. In: Journal of Clinical Investigation. 2004 ; Vol. 113, No. 2. pp. 274-284.
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    CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. / Scott, John W.; Hawley, Simon A.; Green, Kevin A.; Anis, Miliea; Stewart, Greg; Scullion, Gillian A.; Norman, David G.; Hardie, D. Grahame.

    In: Journal of Clinical Investigation, Vol. 113, No. 2, 2004, p. 274-284.

    Research output: Contribution to journalArticle

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