2.A.52 The Ni2+-Co2+ Transporter (NiCoT) Family

Currently sequenced proteins of the NiCoT family are found in Gram-negative and Gram-positive bacteria as well as archaea and eukaryotes. The functionally best characterized members of the family catalyze uptake of Ni2+ and/or Co2+ in a proton motive force-dependent process. These proteins vary in size from 301 to 381 amino acyl residues and possess 7 or 8 TMSs. Topological analyses with the HoxN Ni2+ transporter of Ralstonia eutropha (Alcaligenes eutrophus) suggest that it possesses 8 TMSs with its N- and C-termini in the cytoplasm. The Co2+ (Ni2+) transporter of Rhodococcus rhodochrous, NhlF, exhibits eight putative TMSs, and eight apparent TMSs are revealed by a hydropathy analysis of the multiple alignment of the NiCoT family protein sequences. An HX4DH sequence in helix 2 of the HoxN protein has been implicated in Ni2+ binding, and both helix 1 and helix 2 which interact spatially, form the selectivity filter (Degan and Eitinger, 2002). In the H. pylori NixA homologue, several conserved motifs have been shown to be important for Ni2+ binding and transport (Wolfram and Bauerfeind, 2002).

The overall reaction catalyzed by the proteins of the NiCoT family is:

[Ni2+ or Co2+] (out) [Ni2+ or Co2+] (in)

This family belongs to the Transporter-Opsin-G protein-coupled receptor (TOG) Superfamily.



Adhikary, A., S. Biswal, D. Chatterjee, and A.S. Ghosh. (2022). A NiCoT family metal transporter of (Rv2856/NicT) behaves as a drug efflux pump that facilitates cross-resistance to antibiotics. Microbiology (Reading) 168:.

Degen, O. and T. Eitinger. (2002). Substrate specificity of nickel/cobalt permeases: insights from mutants altered in transmembrane domains I and II. J. Bacteriol. 184: 3569-3577.

Degen, O., M. Kobayashi, S. Shimizu, and T. Eitinger. (1999). Selective transport of divalent cations by transition metal permeases: the Alcaligenes eutrophus HoxN and the Rhodococcus rhodochrous NhlF. Arch. Microbiol. 171: 139-145.

Deng, X., J. He, and N. He. (2013). Comparative study on Ni2+-affinity transport of nickel/cobalt permeases (NiCoTs) and the potential of recombinant Escherichia coli for Ni2+ bioaccumulation. Bioresour Technol 130: 69-74.

Eitinger, T. and B. Friedrich. (1991). Cloning, nucleotide sequence, and heterologous expression of a high-affinity nickel transport gene from Alcaligenes eutrophus. J. Biol. Chem. 266: 3222-3227.

Eitinger, T. and B. Friedrich. (1994). A topological model for the high affinity nickel transporter of Alcaligenes eutrophus. Mol. Microbiol. 12: 1025-1032.

Eitinger, T. and M.-A. Mandrand-Berthelot. (2000). Nickel transport systems in microorganisms. Arch. Microbiol. 173: 1-9.

Eitinger, T., L. Wolfram, O. Degen, and C. Anthon. (1997). A Ni2+ binding motif is the basis of high affinity transport of the Alcaligenes eutrophus nickel permease. J. Biol. Chem. 272: 17139-17144.

Eitinger, T., O. Degen, U. Böhnke, and M. Müller. (2000). Nic1p, a relative of bacterial transition metal permeases in Schizosaccharomyces pombe, provides nickel ion for urease biosynthesis. J. Biol. Chem. 275: 18029-18033.

Eitinger, T., O. Degen, U. Bohnke, and M. Muller. (2000). Nic1p, a relative of bacterial transition metal permeases in schizosaccharomyces pombe, provides nickel ion for urease biosynthesis. J. Biol. Chem. 275: 33184.

Fu, C., S. Javedan, F. Moshiri, and R.J. Maier. (1994). Bacterial genes involved in incorporation of nickel into hydrogenase enzyme. Proc. Natl. Acad. Sci. USA 91: 5099-5103.

Fulkerson, J.F., Jr. and H.L.T. Mobley. (2000). Membrane topology of the NixA nickel transporter of Helicobacter pylori: two nickel transport-specific motifs within transmembrane helices II and III. J. Bacteriol. 182: 1722-1730.

Hebbeln, P. and T. Eitinger. (2004). Heterologous production and characterization of bacterial nickel/cobalt permeases. FEMS Microbiol. Lett. 230: 129-135.

Hernandez, J.A., P.S. Micus, S.A.L. Sunga, L. Mazzei, S. Ciurli, and G. Meloni. (2024). Metal selectivity and translocation mechanism characterization in proteoliposomes of the transmembrane NiCoT transporter NixA from. Chem Sci 15: 651-665.

Iwig, J.S., J.L. Rowe, and P.T. Chivers. (2006). Nickel homeostasis in Escherichia coli - the rcnR-rcnA efflux pathway and its linkage to NikR function. Mol. Microbiol. 62: 252-262.

Komeda, H., M. Kobayashi, and S. Shimizu. (1997). A novel transporter involved in cobalt uptake. Proc. Natl. Acad. Sci. USA 94: 36-41.

Rodrigue, A., G. Effantin, and M.A. Mandrand-Berthelot. (2005). Identification of rcnA (yohM), a nickel and cobalt resistance gene in Escherichia coli. J. Bacteriol. 187: 2912-2916.

Saier, M.H., Jr., B.H. Eng, S. Fard, J. Garg, D.A. Haggerty, W.J. Hutchinson, D.L. Jack, E.C. Lai, H.J. Liu, D.P. Nusinew, A.M. Omar, S.S. Pao, I.T. Paulsen, J.A. Quan, M. Sliwinski, T.-T. Tseng, S. Wachi, and G.B. Young. (1999). Phylogenetic characterization of novel transport protein families revealed by genome analyses. Biochim. Biophys. Acta 1422: 1-56.

Wolfram, L. and P. Bauerfeind. (2002). Conserved low-affinity nickel-binding amino acids are essential for the function of the nickel permease NixA of Helicobacter pylori. J. Bacteriol. 184: 1438-1443.

Wolfram, L., B. Friedrich, and T. Eitinger. (1995). The Alcaligenes eutrophus protein HoxN mediates nickel transport in Escherichia coli. J. Bacteriol. 177: 1840-1843.

Wolfram, L., E. Haas, and P. Bauerfeind. (2006). Nickel represses the synthesis of the nickel permease NixA of Helicobacter pylori. J. Bacteriol. 188: 1245-1250.


TC#NameOrganismal TypeExample

High affinity Ni2+-specific transporter, HoxN (Hebbeln and Eitinger 2004).


HoxN of Ralstonia eutropha


Co2+ transporter, NhlF (also transports Ni2+ with low affinity) (Hebbeln and Eitinger 2004).


NhlF of Rhodococcus rhodochrous


Ni2+ -specific transporter, Nic1p (Eitinger et al. 2000).


Nic1p of Schizosaccharomyces pombe


High affinity Ni2+ uptake porter, NixA.  Transcription is regulated by NixR (Wolfram et al. 2006).  The metal selectivity and translocation mechanism in proteoliposomes of the transmembrane NiCoT transporter NixA from Helicobacter pylori have been reported (Hernandez et al. 2024).


NixA of Helicobacter pylori


NisA of 350 aas and 8 TMSs (Hebbeln and Eitinger 2004; Deng et al. 2013).


NisA of Staphylococcus aureus


HupN of 381 aas and 8 TMSs (Hebbeln and Eitinger 2004; Deng et al. 2013).


HupN of Brandyrhizobium japonicum


NicT is a heavy metal transporter of 372 aas with 8 TMSs in a 4 + 4 TMS arrangement suggesting of a 4 TMS repeat unit.  Actually it looks like a 2 + 2 + 2 + 2 arrangement.  It is a NiCoT family transporter of Mycobacterium tuberculosis (Rv2856/NicT).  It also behaves as a drug efflux pump that facilitates cross-resistance to antibiotics (Adhikary et al. 2022).


NicT of Mycobacterium tuberculosis


Putative high affinity nickel ion uptake transporter of 413 aas and 8 TMSs


Nickel transporter of Neurospora crassa


NicO homologue of 363 aas and 6 TMSs


NicO of Emailiania huxleyi


TC#NameOrganismal TypeExample

Putative Ni2+/Co2+ uptake transporter of 277 aas and 7 TMSs.


Nickel/cobalt transporter of Leptospirillum ferroxidans


Putative Ni2+/Co2+ transporter of 269 aas and 7 TMSs.


Nickel/cobalt transporter of Dechloromonas aromatica


Putative Ni2+/Co2+ uptake porter of 220 aas and 6 TMSs.


Nickel/cobalt porter of Thermus thermophilus


Putative nickel/cobalt porter of 227 aas and 6 TMSs


Ni2+ porter of Deinococcus deserti


Putative transporter of 274 aas and 6 TMSs.


Transporter of Chitinophaga pinensis


NiCoT homologue of 224 aas and 6 TMSs.


NiCoT family member of Gloeobacter violaceus


TC#NameOrganismal TypeExample

TC#NameOrganismal TypeExample