Monovalent cation:proton antiporter-2

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The Monovalent Cation:Proton Antiporter-2 (CPA2) Family (TC# 2.A.37) is a moderately large family of transporters belonging to the CPA superfamily. Members of the CPA2 family have been found in bacteria, archaea and eukaryotes. The proteins of the CPA2 family consist of between 333 and 900 amino acyl residues and exhibit 10-14 transmembrane α-helical spanners (TMSs).[1][2]

Homology

Several organisms possess multiple CPA2 paralogues. Thus, E. coli has three, Methanococcus jannaschii has four and Synechocystis sp. has five paralogues. The potassium efflux system, Kef, protects bacteria against the detrimental effects of electrophilic compounds via acidification of the cytoplasm. Kef is inhibited by glutathione (GSH) but activated by glutathione-S-conjugates (GS-X) formed in the presence of electrophiles. GSH and GS-X bind to overlapping sites on Kef, which are located in a cytosolic regulatory domain.[1]

Function

Among the functionally well-characterized members of the family are:

  1. KefB/KefC K+ efflux proteins of E. coli (i.e., TC# 2.A.37.1.3 and TC# 2.A.37.1.1, respectively), which may be capable of catalyzing both K+/H+ antiport and K+ uniport, depending on conditions [3][4][5]
  2. Na+/H+ antiporter of Enterococcus hirae (i.e., NapA, TC# 2.A.37.2.1) [6]
  3. K+/H+ antiporter of S. cerevisiae (i.e., Kha1, TC# 2.A.37.4.1). It has been proposed that under normal physiological conditions, these proteins may function by essentially the same mechanism.

KefC and KefB of E. coli are responsible for glutathione-gated K+ efflux.[7][8] Each of these proteins consists of a transmembrane hydrophobic N-terminal domain, and a lesser conserved C-terminal hydrophilic domain. Each protein interacts with a second protein encoded by genes that overlap the gene encoding the primary transporter. The KefC ancillary protein is YabF while the KefB ancillary protein is YheR. These ancillary proteins stimulate transport activity about 10-fold.[9] These proteins are important for cell survival during exposure to toxic metabolites, possibly because they can release K+, allowing H+ uptake. Activation of the KefB or KefC K+ efflux system only occurs in the presence of glutathione and a reactive electrophile such as methylglyoxal or N-ethylmaleimide. Formation of the methylglyoxal-glutathione conjugate, S-lactoylglutathione, is catalyzed by glyoxalase I, and S-lactoylglutathione activates KefB and KefC.[10] H+ uptake (acidification of the cytoplasm) accompanying or following K+ efflux may serve as a further protective mechanism against electrophile toxicity.[4][7][8][11] Inhibition of transport by glutathione was enhanced by NADH.[12]

Gram-negative bacteria are protected against toxic electrophilic compounds by glutathione-gated potassium efflux systems (Kef) that modulate cytoplasmic pH. Roosild et al. (2010) have elucidated the mechanism of gating through structural and functional analysis of the E. coli KefC. The revealed mechanism can explain how subtle chemical differences in glutathione derivatives can produce opposite effects on channel function.[13] Kef channels are regulated by potassium transport and NAD-binding (KTN) domains that sense both reduced glutathione, which inhibits Kef activity, and glutathione adducts that form during electrophile detoxification and activate Kef. Roosild et al. (2010) found that reduced glutathione stabilizes an inter-domain association between two KTN folds, whereas large adducts sterically disrupt this interaction. F441 is identified as the pivotal residue discriminating between reduced glutathione and its conjugates. They demonstrated a major structural change on the binding of an activating ligand to a KTN-domain protein.[13]

The MagA protein of Magnetospirillum sp. strain AMB-1 has been reported to be required for synthesis of bacterial magnetic particles. The magA gene is subject to transcriptional activation by an iron deficiency.[14] However, a more recent report has shown that magA mutants of both Magnetospirillum magneticum AMB-1 and M. gryphiswaldense MSR-1 formed wild-type-like magnetosomes without a growth defect.[15] Its transport function is not known. The GerN and GrmA proteins of Bacillus cereus and Bacillus megaterium, respectively, are spore germination proteins that can exchange Na+ for H+ and/or K+.[16] The AmhT homologue of Bacillus pseudofirmus transports both K+ and NH4+, influences ammonium homeostasis, and is required for normal sporulation and germination. The identification of these proteins as members of the CPA2 family reveals that monovalent cation transport is required for Bacillus spore formation and germination.[17]

Transport Reaction

The generalized transport reaction catalyzed by members of the CPA2 family is:

M+ (in) + nH+ (out) ⇌ M+ (out) + nH+ (in).

(The carrier-mediated mode)

Some members may also catalyze:

M+ (in) ⇌ M+ (out).

(The channel-mediated mode)

See also

References

  1. ^ a b Healy J, Ekkerman S, Pliotas C, Richard M, Bartlett W, Grayer SC, Morris GM, Miller S, Booth IR, Conway SJ, Rasmussen T (April 2014). "Understanding the structural requirements for activators of the Kef bacterial potassium efflux system". Biochemistry. 53 (12): 1982–92. doi:10.1021/bi5001118. PMC 4004266. PMID 24601535.
  2. ^ "2.A.37 The Monovalent Cation:Proton Antiporter-2 (CPA2) Family". Transporter Classification Database. Retrieved 2016-03-16.
  3. ^ Bakker EP, Borchard A, Michels M, Altendorf K, Siebers A (September 1987). "High-affinity potassium uptake system in Bacillus acidocaldarius showing immunological cross-reactivity with the Kdp system from Escherichia coli". Journal of Bacteriology. 169 (9): 4342–8. doi:10.1128/jb.169.9.4342-4348.1987. PMC 213750. PMID 2957359.
  4. ^ a b Booth, I.R.; Jones, M.A.; McLaggan, D; Nikolaev, Y (1996). Konings, W.N. (ed.). Bacterial Ion Channels. Vol. 2. New York: Elsevier Press. ISBN 978-0-444-82442-4. {{cite book}}: |work= ignored (help)
  5. ^ Munro AW, Ritchie GY, Lamb AJ, Douglas RM, Booth IR (March 1991). "The cloning and DNA sequence of the gene for the glutathione-regulated potassium-efflux system KefC of Escherichia coli". Molecular Microbiology. 5 (3): 607–16. doi:10.1111/j.1365-2958.1991.tb00731.x. PMID 2046548. S2CID 23871816.
  6. ^ Waser M, Hess-Bienz D, Davies K, Solioz M (March 1992). "Cloning and disruption of a putative NaH-antiporter gene of Enterococcus hirae". The Journal of Biological Chemistry. 267 (8): 5396–400. doi:10.1016/S0021-9258(18)42779-2. PMID 1312090.
  7. ^ a b Ferguson GP, Munro AW, Douglas RM, McLaggan D, Booth IR (September 1993). "Activation of potassium channels during metabolite detoxification in Escherichia coli". Molecular Microbiology. 9 (6): 1297–303. doi:10.1111/j.1365-2958.1993.tb01259.x. PMID 7934942. S2CID 26045169.
  8. ^ a b Ferguson GP, Nikolaev Y, McLaggan D, Maclean M, Booth IR (February 1997). "Survival during exposure to the electrophilic reagent N-ethylmaleimide in Escherichia coli: role of KefB and KefC potassium channels". Journal of Bacteriology. 179 (4): 1007–12. doi:10.1128/jb.179.4.1007-1012.1997. PMC 178791. PMID 9023177.
  9. ^ Miller S, Ness LS, Wood CM, Fox BC, Booth IR (November 2000). "Identification of an ancillary protein, YabF, required for activity of the KefC glutathione-gated potassium efflux system in Escherichia coli". Journal of Bacteriology. 182 (22): 6536–40. doi:10.1128/jb.182.22.6536-6540.2000. PMC 94807. PMID 11053405.
  10. ^ MacLean MJ, Ness LS, Ferguson GP, Booth IR (February 1998). "The role of glyoxalase I in the detoxification of methylglyoxal and in the activation of the KefB K+ efflux system in Escherichia coli". Molecular Microbiology. 27 (3): 563–71. doi:10.1046/j.1365-2958.1998.00701.x. PMID 9489668. S2CID 10720918.
  11. ^ Stumpe, S.; Schlösser, A.; Schleyer, M.; Bakker, E. P. (1996-01-01). "Chapter 21 K+ circulation across the prokaryotic cell membrane: K+-uptake systems". In W.N. Konings, H. R. Kaback and J. S. Lolkema (ed.). Transport Processes in Eukaryotic and Prokaryotic Organisms. Vol. 2. North-Holland. pp. 473–499. doi:10.1016/s1383-8121(96)80062-5. ISBN 9780444824424.
  12. ^ Fujisawa M, Ito M, Krulwich TA (August 2007). "Three two-component transporters with channel-like properties have monovalent cation/proton antiport activity". Proceedings of the National Academy of Sciences of the United States of America. 104 (33): 13289–94. Bibcode:2007PNAS..10413289F. doi:10.1073/pnas.0703709104. PMC 1948933. PMID 17679694.
  13. ^ a b Roosild TP, Castronovo S, Healy J, Miller S, Pliotas C, Rasmussen T, Bartlett W, Conway SJ, Booth IR (November 2010). "Mechanism of ligand-gated potassium efflux in bacterial pathogens". Proceedings of the National Academy of Sciences of the United States of America. 107 (46): 19784–9. Bibcode:2010PNAS..10719784R. doi:10.1073/pnas.1012716107. PMC 2993342. PMID 21041667.
  14. ^ Nakamura C, Kikuchi T, Burgess JG, Matsunaga T (July 1995). "Iron-regulated expression and membrane localization of the magA protein in Magnetospirillum sp. strain AMB-1". Journal of Biochemistry. 118 (1): 23–7. doi:10.1093/oxfordjournals.jbchem.a124884. PMID 8537318.
  15. ^ Uebe R, Henn V, Schüler D (March 2012). "The MagA protein of Magnetospirilla is not involved in bacterial magnetite biomineralization". Journal of Bacteriology. 194 (5): 1018–23. doi:10.1128/JB.06356-11. PMC 3294778. PMID 22194451.
  16. ^ Southworth TW, Guffanti AA, Moir A, Krulwich TA (October 2001). "GerN, an endospore germination protein of Bacillus cereus, is an Na(+)/H(+)-K(+) antiporter". Journal of Bacteriology. 183 (20): 5896–903. doi:10.1128/JB.183.20.5896-5903.2001. PMC 99667. PMID 11566988.
  17. ^ Tani K, Watanabe T, Matsuda H, Nasu M, Kondo M (1996-01-01). "Cloning and sequencing of the spore germination gene of Bacillus megaterium ATCC 12872: similarities to the NaH-antiporter gene of Enterococcus hirae". Microbiology and Immunology. 40 (2): 99–105. doi:10.1111/j.1348-0421.1996.tb03323.x. PMID 8867604. S2CID 7130059.

Further reading

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