2.A.121 The Sulfate Transporter (CysZ) Family

The E. coli CysZ protein has a size of 253 aas with 5 TMS. It is a member of the DUF540 or COG2981 protein family. CysZ mutants are deficient in sulfate assimilation and are believed to be defective for sulfate uptake (Britton et al., 1983Byrne et al., 1988Parra et al., 1983Rückert et al., 2005Aguilar-Barajas et al., 2011). However, a cysZ mutant of Salmonella typhimurium grows normally with 1 mM sulfate (Byrne et al., 1988).  Distant homologues of about the same size are found in numerous bacteria, archaea and eukaryotes (e.g., Q6MVD5 in Neurospora crassa and Q08219 in Saccharomyces cerevisiae), and many organisms have multiple CysZ homologues (Marietou et al. 2018).  These 5 TMS proteins may be distantly related to 5 TMS uptake proteins of the ABC superfamily. The CysZ homologue in Corynebacterium glutamicum is present in the cysteine biosynthetic operon and was proposed to be a sulphate uptake porter (Rückert et al. 2005).

Zhang et al., 2014 reported the purification and functional characterization of the E. coli CysZ protein. Using Isothermal Titration Calorimetry, they observed interactions between CysZ and its substrate, sulfate. CysZ is dedicated to a specific pathway that assimilates sulfate for the synthesis of cysteine. Sulfate uptake via CysZ into E. coli whole cells and proteoliposome was demonstrated, and the cysteine synthesis pathway intermediate, sulfite, interacts directly with CysZ with higher affinity than sulfate. In fact, sulfate transport activity is inhibited by sulfite, suggesting the existence of a feedback inhibition mechanism in which sulfite regulates sulfate uptake by CysZ. Sulfate uptake assays performed at different extracellular pH and in the presence of a proton uncoupler indicated that uptake is driven by the proton gradient (Zhang et al., 2014).

The high resolution CysZ structure has been determined (Assur Sanghai et al. 2018), and SO42- binding and flux experiments have provided insight into the molecular mechanism of CysZ-mediated translocation. CysZ structures from three different bacterial species display a previously unknown fold and have subunits organized with inverted transmembrane topology. CysZ from Pseudomonas denitrificans assembles as a trimer of antiparallel dimers and the CysZ structures from two other species recapitulate dimers from this assembly. Mutational studies highlighted the functional relevance of conserved CysZ residues (Assur Sanghai et al. 2018).

The transport process catalyzed by CysZ is:

H+ + SO42- (out) → H+ + SO42- (in)



Aguilar-Barajas, E., C. Díaz-Pérez, M.I. Ramírez-Díaz, H. Riveros-Rosas, and C. Cervantes. (2011). Bacterial transport of sulfate, molybdate, and related oxyanions. Biometals 24: 687-707.

Assur Sanghai, Z., Q. Liu, O.B. Clarke, M. Belcher-Dufrisne, P. Wiriyasermkul, M.H. Giese, E. Leal-Pinto, B. Kloss, S. Tabuso, J. Love, M. Punta, S. Banerjee, K.R. Rajashankar, B. Rost, D. Logothetis, M. Quick, W.A. Hendrickson, and F. Mancia. (2018). Structure-based analysis of CysZ-mediated cellular uptake of sulfate. Elife 7:.

Bahk, Y.Y., J. Lee, I.H. Cho, and H.W. Lee. (2010). An analysis of an interactome for apoptosis factor, Ei24/PIG8, using the inducible expression system and shotgun proteomics. J Proteome Res 9: 5270-5283.

Britton, P., A. Boronat, D.A. Hartley, M.C. Jones-Mortimer, H.L. Kornberg, and F. Parra. (1983). Phosphotransferase-mediated regulation of carbohydrate utilization in Escherichia coli K12: location of the gsr (tgs) and iex (crr) genes by specialized transduction. J Gen Microbiol 129: 349-356.

Byrne, C.R., R.S. Monroe, K.A. Ward, and N.M. Kredich. (1988). DNA sequences of the cysK regions of Salmonella typhimurium and Escherichia coli and linkage of the cysK regions to ptsH. J. Bacteriol. 170: 3150-3157.

Marietou, A., H. Røy, B.B. Jørgensen, and K.U. Kjeldsen. (2018). Sulfate Transporters in Dissimilatory Sulfate Reducing Microorganisms: A Comparative Genomics Analysis. Front Microbiol 9: 309.

Mork, C.N., D.V. Faller, and R.A. Spanjaard. (2007). Loss of putative tumor suppressor EI24/PIG8 confers resistance to etoposide. FEBS Lett. 581: 5440-5444.

Parra, F., P. Britton, C. Castle, M.C. Jones-Mortimer, and H.L. Kornberg. (1983). Two separate genes involved in sulphate transport in Escherichia coli K12. J Gen Microbiol 129: 357-358.

Rückert, C., D.J. Koch, D.A. Rey, A. Albersmeier, S. Mormann, A. Pühler, and J. Kalinowski. (2005). Functional genomics and expression analysis of the Corynebacterium glutamicum fpr2-cysIXHDNYZ gene cluster involved in assimilatory sulphate reduction. BMC Genomics 6: 121.

Rømer, M.U., L. Larsen, H. Offenberg, N. Brünner, and U.A. Lademann. (2008). Plasminogen activator inhibitor 1 protects fibrosarcoma cells from etoposide-induced apoptosis through activation of the PI3K/Akt cell survival pathway. Neoplasia 10: 1083-1091.

Zhang, L., W. Jiang, J. Nan, J. Almqvist, and Y. Huang. (2014). The Escherichia coli CysZ is a pH dependent sulfate transporter that can be inhibited by sulfite. Biochim. Biophys. Acta. 1838: 1809-1816.


TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample

Sulfate transporter, CysZ.  Part of the cysteine biosynthetic pathway; allosterically inhibited by the biosynthetic intermediate, sulfite (Zhang et al. 2014).


CysZ of E. coli (POA6J3)


CysZ homologue


CysZ homologue of Streptomyces coelicolor


Uncharacterized protein, CysZ homologue.


CysZ homologue of Idiomarina loihiensis


Sulfate uptake porter of 246 aas and 4 or 5 TMSs.  CysZ from Pseudomonas denitrificans assembles as a trimer of antiparallel dimers, and the CysZ structures from two other species recapitulate dimers from this assembly. Mutational studies highlighted the functional relevance of conserved CysZ residues (Assur Sanghai et al. 2018).

CysZ of Pseudomonas denitrificans


TC#NameOrganismal TypeExample

Putative sulfate uptake transporter of 5 TMSs, YAL018c

FungiYAL018c of Saccharomyces cerevisiae (P31379)

Uncharacterized protein of 367 aas and 4 or 5 TMSs

UP of Tremella mesenterica


Uncharacterized protein of 288 aas and 4 or 5 TMSs

UP of Phlebiopsis gigantea


Uncharacterized  protein of 282 aas and 5 TMSs.

UP of Neolentinus lepideus


Uncharacterized protein of 345 aas and 5or 6 TMSs.

UP of Mortierella verticillata


The Rrt8p protein of 342 aas.


Rrt8p of Saccharomyces cerevisiae (Q08219)


Uncharacterized protein of 429 aas and 5 TMSs.


UP of Aspergillus niger (E2PST1)


CysZ homologue


CysZ homologue of Fusarium oxysporum


The YOL047C protein


YOL047C of Saccharomyces cerevisiae (Q08218)


Putative sulfate uptake porter of 288 aas and 4 or 5 TMSs.


CysZ homologue of Neurospora crassa


Uncharacterized protein of 261 aas and 4 or 5 TMSs.

UP of Phytophthora parasitica


Uncharacterized protein of 226 aas and 4 or 5 TMSs.

UP of Ashbya gossypii (Yeast) (Eremothecium gossypii)


Uncharacterized protein of 309 aas and 5 TMSs

UP of Pseudomassariella vexata


TC#NameOrganismal TypeExample

Etoposide-induced protein 2.4, isoform 1, Ei24, or p53-induced gene 8 protein, PIG8.  This protein is a apoptosis/autophagy factor (Rømer et al. 2008; Bahk et al. 2010).


Ei24 or Homo sapiens


Uncharacterized protein

Choanoflagellida (Eukaryote)

CysZ homologue of Monosiga brevicollis


Ei24 superfamily homologue


Ei24 homologue of Arabidopsis thaliana


TC#NameOrganismal TypeExample

The bacterial 4TMS CysZ homologue


CysZ homologue of Campylobacter coli (E0QD93)


5TMS Hypothetical protein, HP


HP of Helicobacter pylori (E6S4S3)


Unnamed protein


Unnamed protein of Bartonella clarridgeiae (E6YFT5)


CysZ homologue


CysZ homologue of Sideroxydans lithotrophicus


Uncharacterized protein of 298 aas and 7 TMSs


UP of Nautilia profundicola


Uncharacterized protein of 231 aas and 5 TMSs


UP of Leptospira interogans


Uncharacterized protein of 389 aas and 11 TMSs


UP of Bacteroides clarus


UP of 279 aas and 8 TMSs

UP of Lokiarchaeum sp. GC14_75