<p>CBS (cystathionine-beta-synthase) domains are small intracellular modules, mostly found in two or four copies within a protein, that occur in a variety of proteins in bacteria, archaea, and eukaryotes [<cite idref="PUB00005461"/>, <cite idref="PUB00043686"/>].</p><p>Tandem pairs of CBS domains can act as binding domains for adenosine derivatives and may regulate the activity of attached enzymatic or other domains [<cite idref="PUB00014845"/>]. In some cases, CBS domains may act as sensors of cellular energy status by being activated by AMP and inhibited by ATP [<cite idref="PUB00014845"/>]. In chloride ion channels, the CBS domains have been implicated in intracellular targeting and trafficking, as well as in protein-protein interactions, but results vary with different channels: in the CLC-5 channel, the CBS domain was shown to be required for trafficking [<cite idref="PUB00014846"/>], while in the CLC-1 channel, the CBS domain was shown to be critical for channel function, but not necessary for trafficking [<cite idref="PUB00014847"/>]. Recent experiments revealing that CBS domains can bind adenosine-containing ligands such ATP, AMP, or S-adenosylmethionine have led to the hypothesis that CBS domains function as sensors of intracellularmetabolites [<cite idref="PUB00014845"/>, <cite idref="PUB00019267"/>].</p> <p>Crystallographic studies of CBS domains have shown that pairs of CBS sequences form a globular domain where each CBS unit adopts a beta-alpha-beta-beta-alpha pattern [<cite idref="PUB00000457"/>]. Crystal structure of the CBS domains of the AMP-activated protein kinase in complexes with AMP and ATP shows that the phosphate groups of AMP/ATP lie in a surface pocket at the interface of two CBS domains, which is lined with basic residues, many of which are associated with disease-causing mutations [<cite idref="PUB00043687"/>]. </p><p>In humans, mutations in conserved residues within CBS domains cause a variety of human hereditary diseases, including (with the gene mutated in parentheses): homocystinuria (cystathionine beta-synthase); 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).</p> Cystathionine beta-synthase, core