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24  structures 1556  species 1  interaction 3290  sequences 8  architectures

Family: BCCT (PF02028)

Summary: BCCT, betaine/carnitine/choline family transporter

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This is the Wikipedia entry entitled "Betaine transporter". More...

Betaine transporter Edit Wikipedia article

BCCT family transporter
BetP 3po3.png
BetP (betaine transporter) from Cornyebacterium glutamicum. PDB 3p03
Identifiers
Symbol BCCT
Pfam PF02028
InterPro IPR000060
TCDB 2.A.15
OPM superfamily 67
OPM protein 3fhx

Proteins of the Betaine/Carnitine/Choline Transporter (BCCT) family (TC# 2.A.15) are found in Gram-negative and Gram-positive bacteria and archaea. The BCCT family is a member a large group of secondary transporters, the APC superfamily. Their common functional feature is that they all transport molecules with a quaternary ammonium group [R-N (CH3)3]. The BCCT family proteins vary in length between 481 and 706 amino acyl residues and possess 12 putative transmembrane α-helical spanners (TMSs). The x-ray structures reveal two 5 TMS repeats with the total number of TMSs being 10. These porters catalyze bidirectional uniport or are energized by pmf-driven or smf-driven proton or sodium ion symport, respectively, or else by substrate:substrate antiport. Some of these permeases exhibit osmosensory and osmoregulatory properties inherent to their polypeptide chains.[1]

Structure

Schulze et al. (2010) reported the structures of the sodium-independent carnitine/butyrobetaine antiporter CaiT from Proteus mirabilis (PmCaiT) at 2.3 Å (2WSW​, 4M8J​) and from E. coli (EcCaiT) at 3.5 Å resolution (SWSX​, 3HFX​).[2]

Most members of the BCCT family are Na+- or H+-dependent, whereas EcCaiT is a Na+- and H+-independent substrate:product antiporter. The three-dimensional architecture of CaiT resembles that of the Na+-dependent transporters LeuT and BetP, but in CaiT, a methionine sulphur takes the place of the Na+ to coordinate the substrate in the central transport site, accounting for Na+ independence. Both CaiT structures (SWSW​, 4M8J​) show the fully open, inward-facing conformation, and thus complete the set of functional states that describe the alternating access mechanism. EcCaiT (SWSX​, 3HFX​) contains two bound butyrobetaine substrate molecules, one in the central transport site, the other in an extracellular binding pocket. In the structure of PmCaiT, a tryptophan side chain occupies the transport site, and access to the extracellular site is blocked. Binding of both substrates to CaiT reconstituted into proteoliposomes is cooperative, with Hill coefficients of up to 1.7, indicating that the extracellular site is regulatory. Schulze et al. (2010) proposed a mechanism whereby the occupied regulatory site increases the binding affinity of the transport site and initiates substrate translocation.[2] Glycine betaine transporters have been found to contain a conserved region with four tryptophans in their central region.[3]

Function

Most secondary-active transporters transport their substrates using an electrochemical ion gradient, but the carnitine transporter (CaiT) is an ion-independent, L-carnitine/gamma-butyrobetaine antiporter. Crystal structures of CaiT from E. coli and Proteus mirabilis revealed the inverted five-transmembrane-helix repeat similar to that in the amino acid/Na+ symporter, LeuT. Kalayil et al. (2013) showed that mutations of arginine 262 (R262) made CaiT Na+-dependent with increased transport activity in the presence of a membrane potential, in agreement with substrate/Na+ cotransport. R262 also plays a role in substrate binding by stabilizing the partly unwound TM1' helix.[4]

Modeling CaiT from P. mirabilis in the outward-open and closed states on the corresponding structures of the related symporter BetP revealed alternating orientations of the buried R262 side chain, which mimic sodium binding and unbinding in the Na+-coupled substrate symporters. A similar mechanism may be operative in other Na+/H+-independent transporters, in which a positively charged amino acid replaces the cotransported cation. The oscillation of the R262 side chain in CaiT indicates how a positive charge triggers the change between outward-open and inward-open conformations.[4]

Transport reactions

The generalized transport reactions catalyzed by members of the BCCT family are:[1]

Substrate (out) + nH+ (out) → Substrate (in) + nH+ (in)
Substrate (out) + Na+ (out) → Substrate (in) + Na+ (in)
Substrate-1 (out) + Substrate-2 (in) → Substrate-1 (in) + Substrate-2 (out)
Substrate (out) ⇌ Substrate (in)
Substrate = a quaternary amine

Other betaine transporters

The mammalian betaine transporter (BGT1; SLC6A12) is predominantly expressed in the liver (hepatocytes).[5] It is also expressed in the kidney[5] where it is regulated by NFAT5 during a response to osmotic stress.[6] Further, BGT1 is also present in the leptomeninges surrounding the brain.[5] Deletion of the BGT1 gene in mice did not appear to have any impact on the tendency to develop epilepsy.[7] This is to be expected considering that BGT1 is expressed at far lower levels than GAT1 and also has lower affinity for GABA. This implies that it is not likely to contribute significantly to the inactivation of the inhibitory neurotransmitter GABA.[7]

See also

References

  1. ^ a b Saier, MH Jr. "2.A.15 The Betaine/Carnitine/Choline Transporter (BCCT) Family". Transporter Classification Database. Saier Lab Bioinformatics Group. 
  2. ^ a b Schulze, S; Köster, S; Geldmacher, U; Terwisscha van Scheltinga, AC; Kühlbrandt, W (September 9, 2010). "Structural basis of Na(+)-independent and cooperative substrate/product antiport in CaiT.". Nature. 467 (7312): 233–6. PMID 20829798. doi:10.1038/nature09310. 
  3. ^ Kempf B, Bremer E, Kappes RM (1996). "Three transport systems for the osmoprotectant glycine betaine operate in Bacillus subtilis: characterization of OpuD". J. Bacteriol. 178 (17): 5071–5079. PMC 178300Freely accessible. PMID 8752321. 
  4. ^ a b Kalayil, S; Schulze, S; Kühlbrandt, W (October 22, 2013). "Arginine oscillation explains Na+ independence in the substrate/product antiporter CaiT.". Proc. Natl. Acad. Sci. U.S.A. 110 (43): 17296–301. PMC 3808595Freely accessible. PMID 24101465. doi:10.1073/pnas.1309071110. 
  5. ^ a b c Zhou Y, Holmseth S, Hua R, Lehre AC, Olofsson AM, Poblete-Naredo I, Kempson SA, Danbolt NC (2012). "The betaine-GABA transporter (BGT1, slc6a12) is predominantly expressed in the liver and at lower levels in the kidneys and at the brain surface". Am J Physiol Renal Physiol. 302 (3): F316–28. PMID 22071246. doi:10.1152/ajprenal.00464.2011. 
  6. ^ Lee SD, Choi SY, Lim SW, Lamitina ST, Ho SN, Go WY, Kwon HM (2011). "TonEBP stimulates multiple cellular pathways for adaptation to hypertonic stress: Organic osmolyte-dependent and -independent pathways". AJP: Renal Physiology. 300 (3): F707–F715. PMC 3064130Freely accessible. PMID 21209002. doi:10.1152/ajprenal.00227.2010. 
  7. ^ a b Lehre AC, Rowley NM, Zhou Y, Holmseth S, Guo C, Holen T, Hua R, Laake P, Olofsson AM, Poblete-Naredo I, Rusakov DA, Madsen KK, Clausen RP, Schousboe A, White HS, Danbolt NC (2011). "Deletion of the betaine-GABA transporter (BGT1; slc6a12) gene does not affect seizure thresholds of adult mice". Epilepsy Res. 95 (1–2): 70–81. PMC 3376448Freely accessible. PMID 21459558. doi:10.1016/j.eplepsyres.2011.02.014. 

This article incorporates text from the public domain Pfam and InterPro IPR000060

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BCCT, betaine/carnitine/choline family transporter Provide feedback

No Pfam abstract.

Literature references

  1. Jung H, Buchholz M, Clausen J, Nietschke M, Revermann A, Schmid R, Jung K;, J Biol Chem. 2002;277:39251-39258. : CaiT of Escherichia coli, a new transporter catalyzing L-carnitine/gamma -butyrobetaine exchange. PUBMED:12163501 EPMC:12163501


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR000060

These prokaryotic transport proteins belong to a family known as BCCT (for Betaine / Carnitine / Choline Transporters) [PUBMED:20923416] and are specific for compounds containing a quaternary nitrogen atom. The BCCT proteins contain 12 transmembrane regionsand are energised by proton symport. They contain a conserved region with four tryptophans in their central region [PUBMED:8752321].

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan APC (CL0062), which has the following description:

This large superfamily contains a variety of transporters including amino acid permeases that according to TCDB belong to the APC (Amino acid-Polyamine-organoCation) superfamily.

The clan contains the following 20 members:

AA_permease AA_permease_2 AA_permease_C Aa_trans BCCT BenE Branch_AA_trans CstA HCO3_cotransp K_trans MFS_MOT1 Na_Ala_symp Nramp SNF Spore_permease SSF Sulfate_transp Transp_cyt_pur Trp_Tyr_perm Xan_ur_permease

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(22933)
Meta
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(392)
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RP55
(3347)
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  Seed
(92)
Full
(3290)
Representative proteomes UniProt
(12224)
NCBI
(22933)
Meta
(1057)
RP15
(392)
RP35
(1697)
RP55
(3347)
RP75
(5576)
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  Seed
(92)
Full
(3290)
Representative proteomes UniProt
(12224)
NCBI
(22933)
Meta
(1057)
RP15
(392)
RP35
(1697)
RP55
(3347)
RP75
(5576)
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Curation and family details

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Seed source: IPR000060
Previous IDs: none
Type: Family
Author: Mian N, Bateman A
Number in seed: 92
Number in full: 3290
Average length of the domain: 463.30 aa
Average identity of full alignment: 34 %
Average coverage of the sequence by the domain: 85.77 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.9 20.9
Trusted cut-off 20.9 20.9
Noise cut-off 20.8 20.8
Model length: 485
Family (HMM) version: 16
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Species distribution

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BCCT

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 BCCT domain has been found. There are 24 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 sequence.

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