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

By J. Scott, S. Hawley, K. Green, Miliea Anis, Greg Stewart, Gillian A. Scullion, D. Norman, D. Hardie. Journal of Clinical Investigation, 2004

757 citations recorded by the source corpus.

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.

Subfields: Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/8d2f75b3b04e57ea51912f5c1dc827a2bade9e6a

How researchers see this paper

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In Molecular Biology

1. D. Hardie
2. R. Shaw
3. David M. Sabatini
4. Bruce E. Kemp
5. David Carling
6. S. Hawley
7. B. Manning
8. Fiona A. Ross

In Surgery

1. D. Hardie
2. R. Shaw
3. David Carling
4. S. Hawley
5. Bruce E. Kemp
6. Fiona A. Ross
7. M. Towler
8. K. Green

Citations in the corpus

• AMPK - a nutrient and energy sensor that maintains energy homeostasis (2012, positive): “Most Bateman domains bind adenosine-containing ligands (usually ATP but in one case S -adenosyl Me”
• AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. (2005, background): “, Wolff-Parkinson-White syndrome (WPWS), which is usually associated with hypertrophic cardiomyopathy (HCM) (Scott et al., 2004).”
• AMP‐activated protein kinase – development of the energy sensor concept (2006, background): “The Bateman domains also bind ATP in a manner that is mutually exclusive with AMP, although their affinity for ATP is lower than that for AMP and much lower than that of the catalytic domain (Scott et al. 2004).”
• The LKB1 tumor suppressor negatively regulates mTOR signaling. (2004, background): “The effect on S6 phosphorylation was also seen under unstimulated conditions in wild-type Lkb1-reconstituted cells (Figure 1B, subunit contains a series of CBS domains that bind AMP (Scott et al., 2004) and, once bound to AMP, induces a conformation lane 2).”
• AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy (2007, background): “When the Bateman domains (that is, CBS1–CBS2 and CBS3–CBS4) from human γ2 were expressed separately, they each bound one molecule of AMP and, as expected from the antagonistic effects of ATP on kinase activation, they also bound ATP in a mutually exclusive manner, although with an affinity that was ”
• Use of Cells Expressing γ Subunit Variants to Identify Diverse Mechanisms of AMPK Activation (2010, background): “We have shown previously that this mutation interferes with the binding to the g2 subunit not only of the activating ligand, AMP, but also of the inhibitory ligand, ATP (Scott et al., 2004).”
• Intrasteric control of AMPK via the γ1 subunit AMP allosteric regulatory site (2004, background): “This has now been extended by direct binding studies by Hardie and colleagues who have shown that each subunit binds 2 moles of AMP with the CBS1/2 and CBS3/4 pairs each contributing a separate binding site (Scott et al. 2003).”
• AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. (2011, background): “These assemble in a pseudosymmetrical manner, such that there are four clefts where adenine nucleotides might bind (Scott et al. 2004; Xiao et al. 2007, 2011).”
• The AMP-activated protein kinase pathway – new players upstream and downstream (2004, background): “All five mutations caused both defective binding of AMP to the isolated Bateman domains (Scott et al., 2004) and defective activation of the intact αβγ complex by AMP (Daniel and Carling, 2002; Scott et al., 2004), and the order of severity of the individual mutations was the same for both…”