Domain in cystathionine beta-synthase and other proteins.
SMART accession number:SM00116
Description: Domain present in all 3 forms of cellular life. Present in two copies in inosine monophosphate dehydrogenase, of which one is disordered in the crystal structure [3]. A number of disease states are associated with CBS-containing proteins including homocystinuria, Becker's and Thomsen disease.
Interpro abstract (IPR000644):

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 [(PUBMED:9020585), (PUBMED:16275737)].

Tandem pairs of CBS domains can act as binding domains for adenosine derivatives and may regulate the activity of attached enzymatic or other domains [(PUBMED:14722619)]. In some cases, CBS domains may act as sensors of cellular energy status by being activated by AMP and inhibited by ATP [(PUBMED:14722619)]. 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 [(PUBMED:14521953)], while in the CLC-1 channel, the CBS domain was shown to be critical for channel function, but not necessary for trafficking [(PUBMED:14718533)]. 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 intracellular metabolites [(PUBMED:14722619), (PUBMED:14722609)].

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 [(PUBMED:10200156)]. 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 [(PUBMED:17851531)].

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).

GO function:protein binding (GO:0005515)
Family alignment:
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There are 29847 CBS domains in 16124 proteins in SMART's nrdb database.

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