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

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 (γ2 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 β-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 β-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

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

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Figure 8

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Model of the N-terminal pair of CBS domains (CBS1 and CBS2) from the γ2 ...
Model of the N-terminal pair of CBS domains (CBS1 and CBS2) from the γ2 subunit of AMPK. The picture is a view of a molecular-surface representation made using the program GRASP (Department of Biochemistry, Columbia University, New York, New York, USA) (51), with CBS1 on the left. The model was made using MODELLER 6 (Department of Biopharmaceutical Sciences, University of California San Francisco, San Francisco, California, USA) (52) and was based on the atomic coordinates of the CBS domain pair from a bacterial IMPDH (Protein Data Bank code 1ZFJ) (34). Electrostatic potential at the surface is depicted as red for negative and blue for positive. The approximate positions of residues mutated in WPWS are shown. R302 and H383 occupy equivalent positions in CBS1 and CBS2, respectively, and are adjacent to each other in the model. Part of residue T400 projects into the hydrophobic cleft between the two domains.