Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95, 5857-5864
Letunic et al. (2012) Nucleic Acids Res , doi:10.1093/nar/gkr931

• HOME
• SETUP
• FAQ
• ABOUT
• GLOSSARY
• WHAT'S NEW
• FEEDBACK

CBS 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:	View or CHROMA formatCLUSTALW formatMSF formatFASTA formatPIR format

There are 29847 CBS domains in 16124 proteins in SMART's nrdb database.

Click on the following links for more information.

• Evolution (species in which this domain is found)

• Click on to expand nodes. To display all proteins with a CBS domain in a specific node, click on it.

  This tree shows only several representative species. The complete taxonomic breakdown of all proteins with CBS domain is also avaliable.

  Useful shortcuts: Expand all nodes or Collapse tree
  Go to specific node: Anopheles gambiae, Arabidopsis thaliana, Caenorhabditis elegans, Drosophila melanogaster, Homo sapiens, Mus musculus, Rattus norvegicus, Saccharomyces cerevisiae, Takifugu rubripes

• Cellular role (predicted cellular role)

• Binding / catalysis: unknown

• Literature (relevant references for this domain)

• Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.

  • Bateman A
  • The structure of a domain common to archaebacteria and the homocystinuria disease protein.
  • Trends Biochem Sci. 1997; 22: 12-3

  • Ponting CP
  • CBS domains in CIC chloride channels implicated in myotonia and nephrolithiasis (kidney stones).
  • J Mol Med. 1997; 75: 160-3

  • Sintchak MD et al.
  • Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid.
  • Cell. 1996; 85: 921-30
  • Display abstract

  • The structure of inosine-5'-monophosphate dehydrogenase (IMPDH) in complex with IMP and mycophenolic acid (MPA) has been determined by X-ray diffraction. IMPDH plays a central role in B and T lymphocyte replication. MPA is a potent IMPDH inhibitor and the active metabolite of an immunosuppressive drug recently approved for the treatment of allograft rejection. IMPDH comprises two domains: a core domain, which is an alpha/beta barrel and contains the active site, and a flanking domain. The complex, in combination with mutagenesis and kinetic data, provides a structural basis for understanding the mechanism of IMPDH activity and indicates that MPA inhibits IMPDH by acting as a replacement for the nicotinamide portion of the nicotinamide adenine dinucleotide cofactor and a catalytic water molecule.

• Disease (disease genes where sequence variants are found in this domain)

• SwissProt sequences and OMIM curated human diseases associated with missense mutations within the CBS domain.

  Protein	Disease
  Cystathionine beta-synthase (P35520) (SMART)	OMIM:236200: Homocystinuria, B6-responsive and nonresponsive types

• Metabolism (metabolic pathways involving proteins which contain this domain)

• Click the image to view the interactive version of the map in iPath

  % proteins involved KEGG pathway ID Description 38.46 map00230 Purine metabolism 11.88 map02010 ABC transporters - General 5.94 map00450 Selenoamino acid metabolism 5.74 map00271 Methionine metabolism 4.87 map00260 Glycine, serine and threonine metabolism 4.87 map05040 Huntington's disease 3.41 map00620 Pyruvate metabolism 3.31 map00710 Carbon fixation 3.12 map00720 Reductive carboxylate cycle (CO2 fixation) 3.12 map00020 Citrate cycle (TCA cycle) 3.02 map00630 Glyoxylate and dicarboxylate metabolism 2.53 map00190 Oxidative phosphorylation 1.85 map00920 Sulfur metabolism 1.75 map04920 Adipocytokine signaling pathway 1.75 map04910 Insulin signaling pathway 1.07 map00272 Cysteine metabolism 0.88 map00051 Fructose and mannose metabolism 0.29 map02020 Two-component system - General 0.29 map03010 Ribosome 0.19 map00650 Butanoate metabolism 0.10 map00910 Nitrogen metabolism 0.10 map00040 Pentose and glucuronate interconversions 0.10 map00790 Folate biosynthesis 0.10 map00071 Fatty acid metabolism 0.10 map00632 Benzoate degradation via CoA ligation 0.10 map00740 Riboflavin metabolism 0.10 map03020 RNA polymerase 0.10 map02060 Phosphotransferase system (PTS) 0.10 map00280 Valine, leucine and isoleucine degradation 0.10 map00240 Pyrimidine metabolism 0.10 map00072 Synthesis and degradation of ketone bodies 0.10 map00310 Lysine degradation 0.10 map01051 Biosynthesis of ansamycins 0.10 map00500 Starch and sucrose metabolism 0.10 map00380 Tryptophan metabolism 0.10 map00480 Glutathione metabolism 0.10 map00640 Propanoate metabolism This information is based on mapping of SMART genomic protein database to KEGG orthologous groups. Percentage points are related to the number of proteins with CBS domain which could be assigned to a KEGG orthologous group, and not all proteins containing CBS domain. Please note that proteins can be included in multiple pathways, ie. the numbers above will not always add up to 100%.

• Structure (3D structures containing this domain)

• 3D Structures of CBS domains in PDB

  PDB code	Main view	Title
  1ak5		Inosine monophosphate dehydrogenase (impdh) from tritrichomonas foetus
  1b3o		Ternary complex of human type-ii inosine monophosphate dehydrogenase with 6-cl-imp and selenazole adenine dinucleotide
  1jcn		Binary complex of human type-i inosine monophosphate dehydrogenase with 6-cl-imp
  1jr1		Crystal structure of inosine monophosphate dehydrogenase in complex with mycophenolic acid
  1me7		Inosine monophosphate dehydrogenase (impdh) from tritrichomonas foetus with rvp and moa bound
  1me8		Inosine monophosphate dehydrogenase (impdh) from tritrichomonas foetus with rvp bound
  1me9		Inosine monophosphate dehydrogenase (impdh) from tritrichomonas foetus with imp bound
  1meh		Inosine monophosphate dehydrogenase (impdh) from tritrichomonas foetus with imp and moa bound
  1mei		Inosine monophosphate dehydrogenase (impdh) from tritrichomonas foetus with xmp and mycophenolic acid bound
  1mew		Inosine monophosphate dehydrogenase (impdh) from tritrichomonas foetus with xmp and nad bound
  1nf7		Ternary complex of the human type ii inosine monophosphate dedhydrogenase with ribavirin monophosphate and c2- mycophenolic adenine dinucleotide
  1nfb		Ternary complex of the human type ii inosine monophosphate dedhydrogenase with 6cl-imp and nad
  1o50		Crystal structure of cbs domain-containing predicted protein (tm0935) from thermotoga maritima at 1.87 a resolution
  1pbj		Cbs domain protein
  1pvm		Crystal structure of a conserved cbs domain protein ta0289 of unknown function from thermoplasma acidophilum
  1vr9		Crystal structure of cbs domain protein/act domain protein (tm0892) from thermotoga maritima at 1.70 a resolution
  1vrd		Crystal structure of inosine-5'-monophosphate dehydrogenase (tm1347) from thermotoga maritima at 2.18 a resolution
  1xkf		Crystal structure of hypoxic response protein i (hrpi) with two coordinated zinc ions
  1y5h		Crystal structure of truncated se-met hypoxic response protein i (hrpi)
  1zfj		Inosine monophosphate dehydrogenase (impdh; ec 1.1.1.205) from streptococcus pyogenes
  2cu0		Crystal structure of inosine-5'-monophosphate dehydrogenase from pyrococcus horikoshii ot3
  2d4z		Crystal structure of the cytoplasmic domain of the chloride channel clc-0
  2ef7		Crystal structure of st2348, a hypothetical protein with cbs domains from sulfolobus tokodaii strain7
  2emq		Hypothetical conserved protein (gk1048) from geobacillus kaustophilus
  2j9l		Cytoplasmic domain of the human chloride transporter clc-5 in complex with atp
  2ja3		Cytoplasmic domain of the human chloride transporter clc-5 in complex with adp
  2nyc		Crystal structure of the bateman2 domain of yeast snf4
  2nye		Crystal structure of the bateman2 domain of yeast snf4
  2o16		Crystal structure of a putative acetoin utilization protein (acub) from vibrio cholerae
  2oox		Crystal structure of the adenylate sensor from amp- activated protein kinase complexed with amp
  2ooy		Crystal structure of the adenylate sensor from amp- activated protein kinase complexed with atp
  2oux		Crystal structure of the soluble part of a magnesium transporter
  2p9m		Crystal structure of conserved hypothetical protein mj0922 from methanocaldococcus jannaschii dsm 2661
  2pfi		Crystal structure of the cytoplasmic domain of the human chloride channel clc-ka
  2qh1		Structure of ta289, a cbs-rubredoxin-like protein, in its fe+2-bound state
  2qlv		Crystal structure of the heterotrimer core of the s. cerevisiae ampk homolog snf1
  2qr1		Crystal structure of the adenylate sensor from amp- activated protein kinase in complex with adp
  2qrc		Crystal structure of the adenylate sensor from amp- activated protein kinase in complex with adp and amp
  2qrd		Crystal structure of the adenylate sensor from amp- activated protein kinase in complex with adp and atp
  2qre		Crystal structure of the adenylate sensor from amp- activated protein kinase in complex with 5-aminoimidazole- 4-carboxamide 1-beta-d-ribofuranotide (zmp)
  2rc3		Crystal structure of cbs domain, ne2398
  2rif		Cbs domain protein pae2072 from pyrobaculum aerophilum complexed with amp
  2rih		Cbs domain protein pae2072 from pyrobaculum aerophilum
  2uv4		Crystal structure of a cbs domain pair from the regulatory gamma1 subunit of human ampk in complex with amp
  2uv5		Crystal structure of a cbs domain pair from the regulatory gamma1 subunit of human ampk in complex with amp
  2uv6		Crystal structure of a cbs domain pair from the regulatory gamma1 subunit of human ampk in complex with amp
  2uv7		Crystal structure of a cbs domain pair from the regulatory gamma1 subunit of human ampk in complex with amp
  2v8q		Crystal structure of the regulatory fragment of mammalian ampk in complexes with amp
  2v92		Crystal structure of the regulatory fragment of mammalian ampk in complexes with atp-amp
  2v9j		Crystal structure of the regulatory fragment of mammalian ampk in complexes with mg.atp-amp
  2yvx		Crystal structure of magnesium transporter mgte
  2yvy		Crystal structure of magnesium transporter mgte cytosolic domain, mg2+ bound form
  2yvz		Crystal structure of magnesium transporter mgte cytosolic domain, mg2+-free form
  2yzi		Crystal structure of uncharacterized conserved protein from pyrococcus horikoshii
  2yzq		Crystal structure of uncharacterized conserved protein from pyrococcus horikoshii
  3ddj		Crystal structure of cbs domain-containing protein in complex with amp (np_344512.1) from sulfolobus solfataricus at 1.80 a resolution
  3fhm		Crystal structure of the cbs-domain containing protein atu1752 from agrobacterium tumefaciens
  3ghd		Crystal structure of a cystathionine beta-synthase domain protein fused to a zn-ribbon-like domain
  3hf7		The crystal structure of a cbs-domain pair with bound amp from klebsiella pneumoniae to 2.75a
  3i8n		A domain of a conserved functionally known protein from vibrio parahaemolyticus rimd 2210633.
  3k6e		Crystal structure of cbs domain protein from streptococcus pneumoniae tigr4

• Links (links to other resources describing this domain)

• INTERPRO	IPR000644

Send comments to Ivica Letunic