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378  structures 5124  species 5  interactions 77225  sequences 464  architectures

Family: CBS (PF00571)

Summary: CBS domain

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CBS domain Edit Wikipedia article

CBS domain
PDB 2nye EBI.png
Structure of the yeast SNF4 protein that contains four CBS domains.[1] This protein is part of the AMP-activated protein kinase (AMPK) complex.
Identifiers
Symbol CBS
Pfam PF00571
InterPro IPR000644
SMART CBS
PROSITE PS51371
SCOP 1zfj
SUPERFAMILY 1zfj
CDD cd02205

In molecular biology, the CBS domain is a protein domain found in a range of proteins in all species from bacteria to man. It was first identified as a conserved sequence region in 1997 and named after cystathionine beta synthase, one of the proteins it is found in.[2] CBS domains are also found in a wide variety of other proteins such as inosine monophosphate dehydrogenase,[3] voltage gated chloride channels[4][5][6][7][8] and AMP-activated protein kinase (AMPK).[9][10] CBS domains regulate the activity of associated enzymatic and transporter domains in response to binding molecules with adenosyl groups such as AMP and ATP, or s-adenosylmethionine.[11]

Structure[edit]

The CBS domain is composed of a beta-alpha-beta-beta-alpha secondary structure pattern that is folded into a globular tertiary structure that contains a three-stranded antiparallel β-sheet with two α-helices on one side. CBS domains are always found in pairs in protein sequences and each pair of these domains tightly associate in a pseudo dimeric arrangement through their β-sheets forming a so-called CBS-pair or Bateman domain.[12][13] These CBS domain pairs can associate in a head-to-head (i.e. PDB codes, 3KPC, 1PVM, 2OOX) or a head-to-tail (i.e. PDB codes 1O50, 1PBJ) manner forming a disk-like compact structure. By doing so, they form clefts that constitute the canonical ligand binding regions.[14][15][16][17][18] In principle, the number of canonical binding sites matches the number of CBS domains within the molecule and are traditionally numbered according to the CBS domain that contains each of the conserved aspartate residues that potentially interact with the ribose of the nucleotides.[19] However, not all of these cavities might necessarily bind nucleotides or be functional. Recently, a non-canonical site for AMP has also been described in protein MJ1225 from M. jannaschii, though its functional role is still unknown.[20]

Multiple sequence alignment of CBS domains showing secondary structures above. Yellow arrows represent beta strands and red boxes alpha helices.

Ligand binding[edit]

It has been shown that CBS domains bind to adenosyl groups in molecules such as AMP and ATP,[11] or s-adenosylmethionine,[21] but they may also bind metallic ions such as Mg2+.[22][23] Upon binding these different ligands the CBS domains regulate the activity of associated enzymatic domains.[24] The molecular mechanisms underlying this regulation are just starting to be elucidated.[16][17][21][22][25] At the moment, two different type of mechanisms have been proposed. The first one claims that the nucleotide portion of the ligand induces essentially no change in the protein structure, the electrostatic potential at the binding site being the most significant property of adenosine nucleotide binding.[17][26] This "static" response would be involved in processes in which regulation by energy charge would be advantageous.[17][26] On the contrary, the second type of mechanism (denoted as "dynamic") involves dramatic conformational changes in the protein structure upon ligand binding and has been reported for the cytosolic domain of the Mg2+ transporter MgtE from Thermus thermophilus,[22] the unknown function protein MJ0100 from M. jannaschii [21][27] and the regulatory region of Clostridium perfringens pyrophosphatase.[28]

Associated domains[edit]

CBS domains are often found in proteins that contain other domains. These domains are usually enzymatic, membrane transporters or DNA-binding domains. However, proteins that contain only CBS domains are also often found, particularly in prokaryotes. These standalone CBS domain proteins might form complexes upon binding to other proteins such as kinases to which they interact with and regulate.

Example protein domains found associated with CBS domains

Mutations leading to disease[edit]

Mutations in some human CBS domain-containing proteins leads to genetic diseases.[3] For example, mutations in the cystathionine-beta-synthase protein lead to an inherited disorder of the metabolism called homocystinuria (OMIM: 236200).[29] Mutations in the gamma subunit of the AMPK enzyme have been shown to lead to familial hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome (OMIM: 600858). Mutations in the CBS domains of the IMPDH enzyme lead to the eye condition retinitis pigmentosa (OMIM: 180105).

Humans have a number of voltage-gated chloride channel genes, and mutations in the CBS domains of several of these have been identified as the cause of genetic diseases. Mutations in CLCN1 lead to myotonia (OMIM: 160800),[30] mutations in CLCN2 can lead to idiopathic generalised epilepsy (OMIM: 600699), mutations in CLCN5 can lead to Dent's disease (OMIM: 300009), mutations in CLCN7 can lead to osteopetrosis (OMIM: 259700),[31] and mutations in CLCNKB can lead to Bartter syndrome (OMIM: 241200).

References[edit]

  1. ^ PDB 2nye; Rudolph MJ, Amodeo GA, Iram SH, Hong SP, Pirino G, Carlson M, Tong L (January 2007). "Structure of the Bateman2 domain of yeast Snf4: dimeric association and relevance for AMP binding". Structure 15 (1): 65–74. doi:10.1016/j.str.2006.11.014. PMID 17223533. 
  2. ^ Bateman A (January 1997). "The structure of a domain common to archaebacteria and the homocystinuria disease protein". Trends Biochem. Sci. 22 (1): 12–3. doi:10.1016/S0968-0004(96)30046-7. PMID 9020585. 
  3. ^ a b Ignoul S, Eggermont J (December 2005). "CBS domains: structure, function, and pathology in human proteins". Am. J. Physiol., Cell Physiol. 289 (6): C1369–78. doi:10.1152/ajpcell.00282.2005. PMID 16275737. 
  4. ^ Ponting CP (March 1997). "CBS domains in CIC chloride channels implicated in myotonia and nephrolithiasis (kidney stones)". J. Mol. Med. 75 (3): 160–3. PMID 9106071. 
  5. ^ Meyer S, Dutzler R (February 2006). "Crystal structure of the cytoplasmic domain of the chloride channel ClC-0". Structure 14 (2): 299–307. doi:10.1016/j.str.2005.10.008. PMID 16472749. 
  6. ^ Yusef YR, Zúñiga L, Catalán M, Niemeyer MI, Cid LP, Sepúlveda FV (April 2006). "Removal of gating in voltage-dependent ClC-2 chloride channel by point mutations affecting the pore and C-terminus CBS-2 domain". J. Physiol. (Lond.) 572 (Pt 1): 173–81. doi:10.1113/jphysiol.2005.102392. PMC 1779660. PMID 16469788. 
  7. ^ Markovic S, Dutzler R (June 2007). "The structure of the cytoplasmic domain of the chloride channel ClC-Ka reveals a conserved interaction interface". Structure 15 (6): 715–25. doi:10.1016/j.str.2007.04.013. PMID 17562318. 
  8. ^ Meyer S, Savaresi S, Forster IC, Dutzler R (January 2007). "Nucleotide recognition by the cytoplasmic domain of the human chloride transporter ClC-5". Nat. Struct. Mol. Biol. 14 (1): 60–7. doi:10.1038/nsmb1188. PMID 17195847. 
  9. ^ Day P, Sharff A, Parra L, et al. (May 2007). "Structure of a CBS-domain pair from the regulatory gamma1 subunit of human AMPK in complex with AMP and ZMP". Acta Crystallogr. D Biol. Crystallogr. 63 (Pt 5): 587–96. doi:10.1107/S0907444907009110. PMID 17452784. 
  10. ^ Rudolph MJ, Amodeo GA, Iram SH, et al. (January 2007). "Structure of the Bateman2 domain of yeast Snf4: dimeric association and relevance for AMP binding". Structure 15 (1): 65–74. doi:10.1016/j.str.2006.11.014. PMID 17223533. 
  11. ^ a b Kemp BE (January 2004). "Bateman domains and adenosine derivatives form a binding contract". J. Clin. Invest. 113 (2): 182–4. doi:10.1172/JCI20846. PMC 311445. PMID 14722609. 
  12. ^ Kemp BE (January 2004). "Bateman domains and adenosine derivatives form a binding contract". J. Clin. Invest. 113 (2): 182–4. doi:10.1172/JCI20846. PMC 311445. PMID 14722609. 
  13. ^ Zhang R, Evans G, Rotella FJ, Westbrook EM, Beno D, Huberman E, Joachimiak A, Collart FR (April 1999). "Characteristics and crystal structure of bacterial inosine-5'-monophosphate dehydrogenase". Biochemistry 38 (15): 4691–700. doi:10.1021/bi982858v. PMID 10200156. 
  14. ^ Rudolph MJ, Amodeo GA, Iram SH, Hong SP, Pirino G, Carlson M, Tong L (January 2007). "Structure of the Bateman2 domain of yeast Snf4: dimeric association and relevance for AMP binding". Structure 15 (1): 65–74. doi:10.1016/j.str.2006.11.014. PMID 17223533. 
  15. ^ Meyer S, Savaresi S, Forster IC, Dutzler R (January 2007). "Nucleotide recognition by the cytoplasmic domain of the human chloride transporter ClC-5". Nat. Struct. Mol. Biol. 14 (1): 60–7. doi:10.1038/nsmb1188. PMID 17195847. 
  16. ^ a b Amodeo GA, Rudolph MJ, Tong L (September 2007). "Crystal structure of the heterotrimer core of Saccharomyces cerevisiae AMPK homologue SNF1". Nature 449 (7161): 492–5. doi:10.1038/nature06127. PMID 17851534. 
  17. ^ a b c d Townley R, Shapiro L (March 2007). "Crystal structures of the adenylate sensor from fission yeast AMP-activated protein kinase". Science 315 (5819): 1726–9. doi:10.1126/science.1137503. PMID 17289942. 
  18. ^ Jin X, Townley R, Shapiro L (October 2007). "Structural insight into AMPK regulation: ADP comes into play". Structure 15 (10): 1285–95. doi:10.1016/j.str.2007.07.017. PMID 17937917. 
  19. ^ Kemp BE, Oakhill JS, Scott JW (October 2007). "AMPK structure and regulation from three angles". Structure 15 (10): 1161–3. doi:10.1016/j.str.2007.09.006. PMID 17937905. 
  20. ^ Gómez-García I, Oyenarte I, Martínez-Cruz LA (May 2010). "The Crystal Structure of Protein MJ1225 from Methanocaldococcus jannaschii Shows Strong Conservation of Key Structural Features Seen in the Eukaryal gamma-AMPK". J Mol Biol 399 (1): 53–70. doi:10.1016/j.jmb.2010.03.045. PMID 20382158. 
  21. ^ a b c Lucas M, Encinar JA, Arribas EA, Oyenarte I, García IG, Kortazar D, Fernández JA, Mato JM, Martínez-Chantar ML, Martínez-Cruz LA (February 2010). "Binding of S-methyl-5'-thioadenosine and S-adenosyl-L-methionine to protein MJ0100 triggers an open-to-closed conformational change in its CBS motif pair". J. Mol. Biol. 396 (3): 800–20. doi:10.1016/j.jmb.2009.12.012. PMID 20026078. 
  22. ^ a b c Ishitani R, Sugita Y, Dohmae N, Furuya N, Hattori M, Nureki O (October 2008). "Mg2+-sensing mechanism of Mg2+ transporter MgtE probed by molecular dynamics study". Proc. Natl. Acad. Sci. U.S.A. 105 (40): 15393–8. doi:10.1073/pnas.0802991105. PMC 2563093. PMID 18832160. 
  23. ^ Hattori M, Nureki O (March 2008). "[Structural basis for the mechanism of Mg2 homeostasis by MgtE transporter]". Tanpakushitsu Kakusan Koso (in Japanese) 53 (3): 242–8. PMID 18326297. 
  24. ^ Scott JW, Hawley SA, Green KA, et al. (January 2004). "CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations". J. Clin. Invest. 113 (2): 274–84. doi:10.1172/JCI19874. PMC 311435. PMID 14722619. 
  25. ^ Tuominen H, Salminen A, Oksanen E, Jämsen J, Heikkilä O, Lehtiö L, Magretova NN, Goldman A, Baykov AA, Lahti R (May 2010). "Crystal structures of the CBS and DRTGG domains of the regulatory region of Clostridiumperfringens pyrophosphatase complexed with the inhibitor, AMP, and activator, diadenosine tetraphosphate". J. Mol. Biol. 398 (3): 400–13. doi:10.1016/j.jmb.2010.03.019. PMID 20303981. 
  26. ^ a b Xiao B, Heath R, Saiu P, Leiper FC, Leone P, Jing C, Walker PA, Haire L, Eccleston JF, Davis CT, Martin SR, Carling D, Gamblin SJ (September 2007). "Structural basis for AMP binding to mammalian AMP-activated protein kinase". Nature 449 (7161): 496–500. doi:10.1038/nature06161. PMID 17851531. 
  27. ^ Lucas M, Kortazar D, Astigarraga E, et al. (October 2008). "Purification, crystallization and preliminary X-ray diffraction analysis of the CBS-domain pair from the Methanococcus jannaschii protein MJ0100". Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun. 64 (Pt 10): 936–41. doi:10.1107/S1744309108027930. PMC 2564890. PMID 18931440. 
  28. ^ Tuominen H, Salminen A, Oksanen E, et al. (May 2010). "Crystal Structures of the CBS and DRTGG Domains of the Regulatory Region of Clostridium perfringens Pyrophosphatase Complexed with the Inhibitor, AMP, and Activator, Diadenosine Tetraphosphate". J Mol Biol 398 (3): 400–413. doi:10.1016/j.jmb.2010.03.019. PMID 20303981. 
  29. ^ Shan X, Dunbrack RL, Christopher SA, Kruger WD (March 2001). "Mutations in the regulatory domain of cystathionine beta synthase can functionally suppress patient-derived mutations in cis". Hum. Mol. Genet. 10 (6): 635–43. doi:10.1093/hmg/10.6.635. PMID 11230183. 
  30. ^ Pusch M (April 2002). "Myotonia caused by mutations in the muscle chloride channel gene CLCN1". Hum. Mutat. 19 (4): 423–34. doi:10.1002/humu.10063. PMID 11933197. 
  31. ^ Cleiren E, Bénichou O, Van Hul E, et al. (December 2001). "Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene". Hum. Mol. Genet. 10 (25): 2861–7. doi:10.1093/hmg/10.25.2861. PMID 11741829. 

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CBS domain Provide feedback

CBS domains are small intracellular modules that pair together to form a stable globular domain [2]. This family represents a single CBS domain. Pairs of these domains have been termed a Bateman domain [6]. CBS domains have been shown to bind ligands with an adenosyl group such as AMP, ATP and S-AdoMet [5]. CBS domains are found attached to a wide range of other protein domains suggesting that CBS domains may play a regulatory role making proteins sensitive to adenosyl carrying ligands. The region containing the CBS domains in Cystathionine-beta synthase is involved in regulation by S-AdoMet [4]. CBS domain pairs from AMPK bind AMP or ATP [5]. The CBS domains from IMPDH and the chloride channel CLC2 bind ATP [5].

Literature references

  1. Bateman A; , Trends Biochem Sci 1997;22:12-13.: The structure of a domain common to archaebacteria and the homocystinuria disease protein. PUBMED:9020585 EPMC:9020585

  2. Zhang R, Evans G, Rotella FJ, Westbrook EM, Beno D, Huberman E, Joachimiak A, Collart FR; , Biochemistry 1999;38:4691-4700.: Characteristics and crystal structure of bacterial inosine-5'-monophosphate dehydrogenase. PUBMED:10200156 EPMC:10200156

  3. Ponting CP; , J Mol Med 1997;75:160-163.: CBS domains in ClC chloride channels implicated in myotonia and nephrolithiasis (kidney stones). PUBMED:9106071 EPMC:9106071

  4. Janosik M, Kery V, Gaustadnes M, Maclean KN, Kraus JP , Biochemistry 2001;40:10625-10633.: Regulation of human cystathionine beta-synthase by S-adenosyl-L-methionine: evidence for two catalytically active conformations involving an autoinhibitory domain in the C-terminal region. PUBMED:11524006 EPMC:11524006

  5. Scott JW, Hawley SA, Green KA, Anis M, Stewart G, Scullion GA, Norman DG, Hardie DG; , J Clin Invest 2004;113:274-284.: CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. PUBMED:14722619 EPMC:14722619

  6. Kemp BE; , J Clin Invest 2004;113:182-184.: Bateman domains and adenosine derivatives form a binding contract. PUBMED:14722609 EPMC:14722609


External database links

This tab holds annotation information from the InterPro database.

InterPro entry 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).

Gene Ontology

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Domain organisation

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Alignments

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(15502)
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(14981)
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(23594)
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External links

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Curation and family details

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Curation View help on the curation process

Seed source: [1]
Previous IDs: none
Type: Domain
Author: Bateman A
Number in seed: 850
Number in full: 77225
Average length of the domain: 57.10 aa
Average identity of full alignment: 19 %
Average coverage of the sequence by the domain: 26.04 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 24.0 16.5
Trusted cut-off 24.0 16.5
Noise cut-off 23.9 16.4
Model length: 57
Family (HMM) version: 23
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Species distribution

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Interactions

There are 5 interactions for this family. More...

MgtE IMPDH MgtE_N CBS DUF1936

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the CBS domain has been found. There are 378 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.

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