1.B.14 The Outer Membrane Receptor (OMR) Family

The OMR family includes a large number of sequenced Gram-negative bacterial outer membrane proteins which form transmembrane pores and transport relatively large molecules from the external milieu to the periplasm in an energized process. Although represented in cyanobacteria, no OMR member has been identified in a Gram-positive bacterium, an archaeon or a eukaryote. Energization of transport across the outer membrane requires a heterotrimeric complex of proteins, the TonB-ExbB-ExbD complex, or in some cases, the TolA-TolQ-TolR complex (TC #10.6). Energization requires the proton motive force (pmf) across the cytoplasmic membrane. In the absence of a pmf or one of the three energy coupling proteins of the complex, the receptor binds its substrate, but transport does not occur. Substrates transported by OMR family members include iron-siderophore complexes, vitamin B12, Cu2+, colicins (group B colicins are transported via TonB-dependent receptors while group A colicins are transported via TolA-dependent receptors), and the DNA of various phage. OMR proteins are also essential for the utilization of iron from eukaryotic proteins such as transferrin, hemoglobin and hemin. The vitamin B12, and iron-siderophore receptors feed into ABC-type permeases (TC #3.A.1.13 and 3.A.1.14) for transport across the cytoplasmic membrane. Alteration (e.g., small internal deletions) of some OMR members can convert them into diffusion channels. Normally, they probably form ligand-specific and energy-gated pores through the outer membranes of Gram-negative bacteria. However, the fact that minor genetic changes result in the generation of diffusion channels suggests that these proteins form large porin-like β-barrel structures.

The three-dimensional structure of one OMR family member, FhuA (TC #1.B.14.1.4), has been elucidated in two conformations, one with and one without bound ferrichrome-iron, both at about 2.6 Å resolution (see Ferguson and Deisenhofer (2004) for a review summarizing function/structure relationships). FhuA is a β-barrel composed of 22 antiparallel β-strands. In contrast to the trimeric arrangement seen in many porins, FhuA is monomeric. Located within the β-barrel is a domain called the 'cork' which consists of a four-stranded β-sheet and four short α-helices. The cork closes the channel, but without the cork, there is no activity (Braun et al., 2003). The barrel and cork can be synthesized as separate polypeptide chains, and activity is still observed. The β-barrel is made first, and the cork is inserted later, extracytoplasmically (Braun et al., 2003). A single lipopolysaccharide is tightly associated with the transmembrane region of FhuA. Upon binding of ferrichrome-iron in an aromatic pocket near the cell surface, conformational changes are transduced to the periplasmic face of FhuA, signaling ligand-loading. Based on these findings, a structural model for TonB-dependent, FhuA-mediated siderophore-iron transport across the outer membrane of E. coli has been proposed. Substrate binding induces long-range structural changes that involve gating (Braun and Braun, 2002). Moreover, a ternary complex of FhuA, TonB and FhuD (the periplasmic ABC-type binding receptor) has been demonstrated (Carter et al., 2006). FhuD accepts ferrichrome from FhuA and passes it on to its ABC transporter. Some of these transporters are involved in siderophore-mediated signaling cascades that sense signals at the cell surface and control transcription of genes encoding proteins for siderophore transport and biosynthesis (Braun and Braun, 2002).

Three structures of the Serratia marcescens receptor, HasR (1.B.14.5.1) in complex with its hemophore HasA, have been solved (Krieg et al., 2009). The transfer of heme over a distance of 9 Å from its high-affinity site in HasA into a site of lower affinity in HasR is coupled with the exergonic  formation of the 2 protein complex. Upon docking to the receptor, 1 of the 2 axial heme coordinations of the hemophore is initially broken, but the position and orientation of the heme is preserved. Subsequently, steric displacement of heme by a receptor residue ruptures the other axial coordination, leading to heme transfer into the receptor (Krieg et al., 2009).

OprC of Pseudomonas aeruginosa and NosA of P. stutzeri are two large outer membrane receptors that exhibit copper-binding (Kd = 2.6 µM), channel-forming, and Cu2+ transporting characteristics. Liposome swelling assays with the purified protein and planar bilayer ion conductance measurements suggested that OprC forms small channels after the precursor form (723 aas) is processed to the mature form (668 aas). NosA of P. stutzeri is 65% identical to OprC, and it conveys Cu2+ to intracellular acceptors. OprC synthesis is repressed by exogenous Cu2+ and derepressed by anaerobiosis in the presence of nitrate, results consistent with the conclusion that both it and NosA are involved in copper utilization.

Both one- and two-component TonB-dependent transport systems are known. Most OMRs are single-component systems and are analogous to the well-characterized siderophore receptors (TC #1.B.14.1.1-1.B.14.1.4 below). Two component systems consist of a TonB-dependent receptor homologous to those of the one component systems as well as an accessory lipoprotein. The HpuAB pair (TC #1.B.14.2.3) is one example of such a system, while the TbpAB (TC #1.B.14.2.12) and the LbpAB (TC #1.B.14.2.4) systems are two other examples. The LbpB and TbpB lipoproteins are homologous, but the smaller HpuA lipoprotein is not demonstrably homologous to either LbpB or TbpB.

The HasR receptors of Serratia marcescens and Pseudomonas aeruginosa use an extracellular processed haemophore, HasA, that captures free or haemoglobin-bound haem and shuttles it to HasR in preparation for transport across the outer membrane by a TonB-dependent mechanism. HasA is a monomeric protein that binds haem with very high affinity (Kd lower than 10-8 M) and binds HasR both in the heme-free and heme-loaded forms with a Kd of about 10-10 M. It is exported via an ABC-type export system. The iron-regulated iron-siderophore yersiniabactin receptors are also the pesticin receptors of Yersinia species which provide the entry route of the bacteriocin, pesticin.

Wolff et al. (2007) reported the 3-D NMR structure of apoHasA (TC# 1.A.14.5.1) and the backbone dynamics of both loaded and unloaded hemophore. While the overall structure of HasA is very similar in the apo and holo forms, the hemophore presents a transition from an open to a closed form upon ligand binding, through a large movement of up to 30 Å, of loop L1 bearing H32. Comparison of loaded and unloaded HasA dynamics on different time scales revealed striking flexibility changes in the binding pocket. These features provide the dual function of heme binding and release to the HasR receptor (Wolff et al., 2007).

The structure of the BtuB outer membrane receptor (OMR; 1.B.14.3.1) and the FhuA OMR (1.B.14.1.2) complexed with the C-terminal domain of TonB (2.C.1.1.1), the energy transmitter to the OMR from the ExbBD energizer, shows TonB binding to the TonB box in the OMRs. TonB binding causes the TonB box to form a β-strand, forming a β-sheet with TonB's own β-strand. This is consistent with a mechanical 'pulling' mechanism of transport (Shultis et al., 2006). The conserved TonB arginine 166 is oriented to form multiple contacts with the FhuA 'cork', the globublar domain enclosed by the β-barrel (Pawelek et al., 2006).

Transport results from energy-driven movement of the TonB protein, which either pulls the plug out of the barrel or causes it to rearrange within the barrel. Udho et al. (2009) discovered that if the cis solution contains 4 M urea, then, with the periplasmic side of the channel facing that solution, macroscopic conductances and single channel events can be observed with FhuA, Cir, and BtuB. Channels generated by 4 M urea exposure were not a consequence of general protein denaturation as their ligand-binding properties were preserved. Thus, with FhuA, addition of ferrichrome (its siderophore) to the trans, extracellular-facing side reversibly inhibited 4 M urea-induced channel opening while blocking the channel (Shultis et al., 2006). With Cir, addition of colicin Ia (the microbial toxin that targets Cir) to the trans, extracellular-facing side, prevented 4 M urea-induced channel opening. Maybe 4 M urea reversibly unfolds the plugs, thereby opening an ion-conducting pathway through these channels. This might mimic the in vivo action of TonB on these plugs (Udho et al., 2009).

TonB-dependent transporters bind and transport ferric chelates, vitamin B12, nickel complexes, and carbohydrates. The transport process requires energy in the form of the pmf and the TonB-ExbB-ExbD complex to transduce this energy to the outer membrane. The siderophore substrates range in complexity from simple small molecules such as citrate to large proteins such as serum transferrin and hemoglobin. Expression can be regulated by metal-dependent regulators, σ/anti-σ factors, small RNAs, and a riboswitch (Noinaj et al., 2010). Noinaj et al. (2010) summarized the regulation, structure and function of these systems.

The generalized transport reaction for proteins of the OMR family is:

Substrate (out)  Substrate (periplasm)

This family belongs to the Outer Membrane Pore-forming Protein I (OMPP-I) Superfamily .



Abel, S., M. Marchi, J. Solier, S. Finet, K. Brillet, and F. Bonneté. (2020). Structural insights into the membrane receptor ShuA in DDM micelles and in a model of gram-negative bacteria outer membrane as seen by SAXS and MD simulations. Biochim. Biophys. Acta. Biomembr 183504. [Epub: Ahead of Print]

Adams, H., G. Zeder-Lutz, I. Schalk, F. Pattus, and H. Celia. (2006). Interaction of TonB with the outer membrane receptor FpvA of Pseudomonas aeruginosa. J. Bacteriol. 188: 5752-5761.

Alice, A.F., C.S. Lopez, C.A. Lowe, M.A. Ledesma, and J.H. Crosa. (2006). Genetic and transcriptional analysis of the siderophore malleobactin biosynthesis and transport genes in the human pathogen Burkholderia pseudomallei K96243. J. Bacteriol. 188: 1551-1566.

Amarelle, V., M.R. O'Brian, and E. Fabiano. (2008). ShmR is essential for utilization of heme as a nutritional iron source in Sinorhizobium meliloti. Appl. Environ. Microbiol. 74: 6473-6475.

Baysse, C., J.-M. Meyer, P. Plesiat, V. Geoffroy, Y. Michel-Briand, and P. Cornelis. (1999). Uptake of pyocin S3 occurs through the outer membrane ferripyoverdine type II receptor of Pseudomonas aeruginosa. J. Bacteriol. 181: 3849-3851.

Benevides-Matos N. and Biville F. (2010). The Hem and Has haem uptake systems in Serratia marcescens. Microbiology. 156(Pt 6):1749-57.

Benevides-Matos, N., C. Wandersman, and F. Biville. (2008). HasB, the Serratia marcescens TonB paralog, is specific to HasR. J. Bacteriol. 190(1):21-7.

Benoit, S.L., S. Seshadri, R. Lamichhane-Khadka, and R.J. Maier. (2013). Helicobacter hepaticus NikR controls urease and hydrogenase activities via the NikABDE and HH0418 putative nickel import proteins. Microbiology 159: 136-146.

Bhat, S., X. Zhu, R.P. Patel, R. Orlando, and L.J. Shimkets. (2011). Identification and localization of Myxococcus xanthus porins and lipoproteins. PLoS One 6: e27475.

Braud, A., M. Hannauer, G.L. Mislin, and I.J. Schalk. (2009). The Pseudomonas aeruginosa pyochelin-iron uptake pathway and its metal specificity. J. Bacteriol. 191: 3517-3525.

Braun, M., F. Endriss, H. Killmann, and V. Braun. (2003). In vivo reconstitution of the FhuA transport protein of Escherichia coli K-12. J. Bacteriol. 185: 5508-5518.

Braun, V. and H. Killmann. (1999). Bacterial solutions to the iron-supply problem. Trends Biochem. Sci. 24: 104-109.

Braun, V. and M. Braun. (2002). Iron transport and signaling in Escherichia coli. FEBS Lett. 529: 78-85.

Braun, V., A. Pramanik, T. Gwinner, M. Köberle, and E. Bohn. (2009). Sideromycins: tools and antibiotics. Biometals 22: 3-13.

Braun, V., H. Pilsl, and P. Gross. (1994). Colicins: structures, modes of action, transfer through membranes and evolution. Arch. Microbiol. 161: 199-206.

Braun, V., K. Hantke, and W. Köster. (1998). Bacterial iron transport: mechanisms, genetics, and regulation. In Metal Ions in Biological Systems, Vol. 35, Chapter 3, A. Sigel and H. Sigel (Eds.), Marcel Dekker, Inc., New York.

Brickman, T.J., C.K. Vanderpool, and S.K. Armstrong. (2006). Heme transport contributes to in vivo fitness of Bordetella pertussis during primary infection in mice. Infect. Immun. 74: 1741-1744.

Brooks, C.L., E. Arutyunova, and M.J. Lemieux. (2014). The structure of lactoferrin-binding protein B from Neisseria meningitidis suggests roles in iron acquisition and neutralization of host defences. Acta Crystallogr F Struct Biol Commun 70: 1312-1317.

Butterton, J.R., J.A. Stoebner, S.M. Payne, and S.B. Calderwood. (1992). Cloning, sequencing, and transcriptional regulation of viuA, the gene encoding the ferric vibriobactin receptor of Vibrio cholerae. J. Bacteriol. 174: 3729-3738.

Cadieux, N., N. Barekzi, and C. Bradbeer. (2007). Observations on the Calcium Dependence and Reversibility of Cobalamin Transport across the Outer Membrane of Escherichia coli. J. Biol. Chem. 282(48): 34921-34928.

Carrizo-Chávez, M.A., A. Cruz-Castañeda, and J.d.e.J. Olivares-Trejo. (2012). The frpB1 gene of Helicobacter pylori is regulated by iron and encodes a membrane protein capable of binding haem and haemoglobin. FEBS Lett. 586: 875-879.

Carswell, C.L., M.D. Rigden, and J.E. Baenziger. (2008). Expression, purification, and structural characterization of CfrA, a putative iron transporter from Campylobacter jejuni. J. Bacteriol. 190: 5650-5662.

Carter, D.M., I.R. Miousse, J.N. Gagnon, E. Martinez, A. Clements, J. Lee, M.A. Hancock, H. Gagnon, P.D. Pawelek, and J.W. Coulton. (2006). Interactions between TonB from Escherichia coli and the periplasmic protein FhuD. J. Biol. Chem. 281: 35413-35424.

Cho, K.H. and A.A. Salyers. (2001). Biochemical analysis of interactions between outer membrane proteins that contribute to starch utilization by Bacteroides thetaiotaomicron. J. Bacteriol. 183: 7224-7230.

Cobessi, D., A. Meksem, and K. Brillet. (2010). Structure of the heme/hemoglobin outer membrane receptor ShuA from Shigella dysenteriae: heme binding by an induced fit mechanism. Proteins 78: 286-294.

Cobessi, D., H. Celia, and F. Pattus. (2005). Crystal structure at high resolution of ferric-pyochelin and its membrane receptor FptA from Pseudomonas aeruginosa. J. Mol. Biol. 352: 893-904.

Cobessi, D., H. Celia, N. Folschweiller, I.J. Schalk, M.A. Abdallah, and F. Pattus. (2005). The crystal structure of the pyoverdine outer membrane receptor FpvA from Pseudomonas aeruginosa at 3.6 angstroms resolution. J. Mol. Biol. 347: 121-134.

Curtis, M.A., S.A. Hanley, and J. Aduse-Opoku. (1999). The rag locus of Porphyromonas gingivalis: a novel pathogenicity island. J Periodontal Res 34: 400-405.

Curtis, N.A., R.L. Eisenstadt, S.J. East, R.J. Cornford, L.A. Walker,and A.J. White. (1988). Iron-regulated outer membrane proteins of Escherichia coli K-12 and mechanism of action of catechol-substituted cephalosporins. Antimicrob. Agents Chemother. 32: 1879-1886.

Danielli, A., S. Romagnoli, D. Roncarati, L. Costantino, I. Delany, and V. Scarlato. (2009). Growth phase and metal-dependent transcriptional regulation of the fecA genes in Helicobacter pylori. J. Bacteriol. 191: 3717-3725.

Destoumieux-Garzón, D., J. Peduzzi, X. Thomas, C. Djediat, and S. Rebuffat. (2006). Parasitism of iron-siderophore receptors of Escherichia coli by the siderophore-peptide microcin E492m and its unmodified counterpart. Biometals 19: 181-191.

Eisenbeis, S., S. Lohmiller, M. Valdebenito, S. Leicht, and V. Braun. (2008). NagA-dependent uptake of N-acetyl-glucosamine and N-acetyl-chitin oligosaccharides across the outer membrane of Caulobacter crescentus. J. Bacteriol. 190: 5230-5238.

Ferguson, A.D. and J. Deisenhofer. (2004). Metal import through microbial membranes. Cell 116: 15-24.

Ferguson, A.D., E. Hofmann, J.W. Coulton, K. Diederichs, and W. Welte. (1998). Siderophore-mediated iron transport: crystal structure of FhuA with bound lipopolysaccharide. Science 282: 2215-2220.

Ferreira, M.J. and I. Sá-Nogueira. (2010). A multitask ATPase serving different ABC-type sugar importers in Bacillus subtilis. J. Bacteriol. 192: 5312-5318.

Fetherston, J.D., J.W. Lillard, Jr., and R.D. Perry. (1995). Analysis of the pesticin receptor from Yersinia pestis: role in iron-deficient growth and possible regulation by its siderophore. J. Bacteriol. 177: 1824-1833.

Foley, M.H., E.C. Martens, and N.M. Koropatkin. (2018). SusE facilitates starch uptake independent of starch binding in B. thetaiotaomicron. Mol. Microbiol. 108: 551-566.

Folschweiller, N., I.J. Schalk, H. Celia, B. Kieffer, M.A. Abdallah, and F. Pattus. (2000). The pyoverdin receptor FpvA, a TonB-dependent receptor involved in iron uptake by Pseudomonas aeruginosa. Mol. Membr. Biol. 17: 123-133.

Forman, S., M.J. Nagiec, J. Abney, R.D. Perry, and J.D. Fetherston. (2007). Analysis of the aerobactin and ferric hydroxamate uptake systems of Yersinia pestis. Microbiology. 153: 2332-2341.

Franza, T., B. Mahé, and D. Expert. (2005). Erwinia chrysanthemi requires a second iron transport route dependent of the siderophore achromobactin for extracellular growth and plant infection. Mol. Microbiol. 55: 261-275.

Fuller-Schaefer, C.A. and R.J. Kadner. (2005). Multiple extracellular loops contribute to substrate binding and transport by the Escherichia coli cobalamin transporter BtuB. J. Bacteriol. 187: 1732-1739.

Fusco WG., Choudhary NR., Council SE., Collins EJ. and Leduc I. (2013). Mutational analysis of hemoglobin binding and heme utilization by a bacterial hemoglobin receptor. J Bacteriol. 195(13):3115-23.

Gao, P., K. Guo, Q. Pu, Z. Wang, P. Lin, S. Qin, N. Khan, J. Hur, H. Liang, and M. Wu. (2020). Impairs Host Defense by Increasing the Quorum-Sensing-Mediated Virulence of. Front Immunol 11: 1696.

Gouaux, E. (1997). The long and short of colicin action: the molecular basis for the biological activity of channel-forming colicins. Structure 5: 313-317.

Gregson, B.H., G. Metodieva, M.V. Metodiev, P.N. Golyshin, and B.A. McKew. (2018). Differential Protein Expression During Growth on Medium Versus Long-Chain Alkanes in the Obligate Marine Hydrocarbon-Degrading Bacterium MIL-1. Front Microbiol 9: 3130.

Grinter, R. and T. Lithgow. (2019). Determination of the molecular basis for coprogen import by Gram-negative bacteria. IUCrJ 6: 401-411.

Hancock, V., L. Ferrières, and P. Klemm. (2008). The ferric yersiniabactin uptake receptor FyuA is required for efficient biofilm formation by urinary tract infectious Escherichia coli in human urine. Microbiology. 154: 167-175.

Hantke, K. (1983). Identification of an iron uptake system specific for coprogen and rhodotorulic acid in Escherichia coli K12. Mol. Gen. Genet. 191: 301-306.

Hantke, K., (1990). Dihydroxybenzoylserine--a siderophore for E. coli. FEMS Microbiol, Lett. 55: 5-8.

Ito, A., T. Sato, M. Ota, M. Takemura, T. Nishikawa, S. Toba, N. Kohira, S. Miyagawa, N. Ishibashi, S. Matsumoto, R. Nakamura, M. Tsuji, and Y. Yamano. (2018). Antibacterial Properties of Cefiderocol, a Novel Siderophore Cephalosporin, against Gram-Negative Bacteria. Antimicrob. Agents Chemother. 62:.

Izadi-Pruneyre, N., F. Huché, G.S. Lukat-Rodgers, A. Lecroisey, R. Gilli, K.R. Rodgers, C. Wandersman, and P. Delepelaire. (2006). The heme transfer from the soluble HasA hemophore to its membrane-bound receptor HasR is driven by protein-protein interaction from a high to a lower affinity binding site. J. Biol. Chem. 281: 25541-25550.

Jakes, K.S. and A. Finkelstein. (2010). The colicin Ia receptor, Cir, is also the translocator for colicin Ia. Mol. Microbiol. 75: 567-578.

Joglekar, P., E.D. Sonnenburg, S.K. Higginbottom, K.A. Earle, C. Morland, S. Shapiro-Ward, D.N. Bolam, and J.L. Sonnenburg. (2018). Genetic Variation of the SusC/SusD Homologs from a Polysaccharide Utilization Locus Underlies Divergent Fructan Specificities and Functional Adaptation in Strains. mSphere 3:.

Kato, S., T. Osaki, S. Kamiya, X.S. Zhang, and M.J. Blaser. (2017). Helicobacter pylori sabA gene is associated with iron deficiency anemia in childhood and adolescence. PLoS One 12: e0184046.

Killmann, H., R. Benz, and B. Braun. (1993). Conversion of the FhuA transport protein into a diffusion channel through the outer membrane of Escherichia coli. EMBO J. 12: 3007-3016.

Kornreich-Leshem, H., C. Ziv, E. Gumienna-Kontecka, R. Arad-Yellin, Y. Chen, M. Elhabiri, A.M. Albrecht-Gary, Y. Hadar, and A. Shanzer. (2005). Ferrioxamine B analogues: targeting the FoxA uptake system in the pathogenic Yersinia enterocolitica. J. Am. Chem. Soc. 127: 1137-1145.

Krieg, S., F. Huché, K. Diederichs, N. Izadi-Pruneyre, A. Lecroisey, C. Wandersman, P. Delepelaire, and W. Welte. (2009). Heme uptake across the outer membrane as revealed by crystal structures of the receptor-hemophore complex. Proc. Natl. Acad. Sci. USA 106: 1045-1050.

López, C.S. and J.H. Crosa. (2007). Characterization of ferric-anguibactin transport in Vibrio anguillarum. Biometals 20: 393-403.

Leach, L.H. and T.A. Lewis. (2006). Identification and characterization of Pseudomonas membrane transporters necessary for utilization of the siderophore pyridine-2,6-bis(thiocarboxylic acid) (PDTC). Microbiology 152: 3157-3166.

Lefèvre, J., P. Delepelaire, M. Delepierre, and N. Izadi-Pruneyre. (2008). Modulation by substrates of the interaction between the HasR outer membrane receptor and its specific TonB-like protein, HasB. J. Mol. Biol. 378: 838-849.

Létoffé, S., F. Nato, M.E. Goldberg, and C. Wandersman. (1999). Interactions of HasA, a bacterial haemophore, with haemoglobin and with its outer membrane receptor HasR. Mol. Microbiol. 33: 546-555.

Létoffé, S., K. Omori, and C. Wandersman. (2000). Functional characterization of the HasAPF hemophore and its truncated and chimeric variants: determination of a region involved in binding to the hemophore receptor. J. Bacteriol. 182: 4401-4405.

Lewis, L.A., M. Gipson, K. Hartman, T. Ownbey, J. Vaughn, and D.W. Dyer. (1999). Phase variation of HpuAB and HmbR, two distinct haemoglobin receptors of Neisseria meningitidis DNM2. Mol. Microbiol. 32: 977-989.

Lewis, L.A., M.-H. Sung, M. Gipson, K. Hartman, and D.W. Dyer. (1998). Transport of intact porphyrin by HpuAB, the hemoglobin-haptoglobin utilization system of Neisseria meningitidis. J. Bacteriol. 180: 6043-6047.

Li, P., H. Lin, Z. Mi, Y. Tong, and J. Wang. (2018). vB_EcoS_IME347 a novel T1-like Escherichia coli bacteriophage. J Basic Microbiol. [Epub: Ahead of Print]

Locher, K.P., B. Rees, R. Koebnik, A. Mitschler, L. Moulinier, J.P. Rosenbusch, and D. Moras. (1998). Transmembrane signaling across the ligand-gated FhuA receptor: crystal structures of free and ferrichrome-bound states reveal allosteric changes. Cell 95: 771-778.

Lohmiller, S., K. Hantke, S.I. Patzer, and V. Braun. (2008). TonB-dependent maltose transport by Caulobacter crescentus. Microbiology 154: 1748-1754.

Lukasik, S.M., K.W. Ho, and D.S. Cafiso. (2007). Molecular basis for substrate-dependent transmembrane signaling in an outer-membrane transporter. J. Mol. Biol. 370: 807-811.

Lynch, D., J. O’Brien, T. Welch, P. Clarke, P.O. Cuív, J.H. Crosa, and M. O’Connell. (2001). Genetic organization of the region encoding regulation, biosynthesis, and transport of rhizobactin 1021, a siderophore produced by Sinorhizobium meliloti. J. Bacteriol. 183: 2576-2585.

Ma, L., W. Kaserer, R. Annamalai, D.C. Scott, B. Jin, X. Jiang, Q. Xiao, H. Maymani, L.M. Massis, L.C. Ferreira, S.M. Newton, and P.E. Klebba. (2007). Evidence of ball-and-chain transport of ferric enterobactin through FepA. J. Biol. Chem. 282: 397-406.

Majumdar, A., V. Trinh, K.J. Moore, C.R. Smallwood, A. Kumar, T. Yang, D.C. Scott, N.J. Long, S.M. Newton, and P.E. Klebba. (2020). Conformational rearrangements in the N-domain of FepA during ferric enterobactin transport. J. Biol. Chem. [Epub: Ahead of Print]

Malki, I., C. Simenel, H. Wojtowicz, G. Cardoso de Amorim, A. Prochnicka-Chalufour, S. Hoos, B. Raynal, P. England, A. Chaffotte, M. Delepierre, P. Delepelaire, and N. Izadi-Pruneyre. (2014). Interaction of a Partially Disordered Antisigma Factor with Its Partner, the Signaling Domain of the TonB-Dependent Transporter HasR. PLoS One 9: e89502.

Marshall, B., A. Stintzi, C. Gilmour, J.M. Meyer, and K. Poole. (2009). Citrate-mediated iron uptake in Pseudomonas aeruginosa: involvement of the citrate-inducible FecA receptor and the FeoB ferrous iron transporter. Microbiology 155: 305-315.

Michel, L., A. Bachelard, and C. Reimmann. (2007). Ferripyochelin uptake genes are involved in pyochelin-mediated signalling in Pseudomonas aeruginosa. Microbiology 153: 1508-1518.

Mokdad, A., D.Z. Herrick, A.K. Kahn, E. Andrews, M. Kim, and D.S. Cafiso. (2012). Ligand-Induced Structural Changes in the Escherichia coli Ferric Citrate Transporter Reveal Modes for Regulating Protein-Protein Interactions. J. Mol. Biol. 423: 818-830.

Morin, N., I. Lanneluc, N. Connil, M. Cottenceau, A.M. Pons, and S. Sablé. (2011). Mechanism of Bactericidal Activity of Microcin L in Escherichia coli and Salmonella enterica. Antimicrob. Agents Chemother. 55: 997-1007.

Nader, M., L. Journet, A. Meksem, L. Guillon, and I.J. Schalk. (2011). Mechanism of ferripyoverdine uptake by Pseudomonas aeruginosa outer membrane transporter FpvA: no diffusion channel formed at any time during ferrisiderophore uptake. Biochemistry 50: 2530-2540.

Nader, M., W. Dobbelaere, M. Vincent, L. Journet, H. Adams, D. Cobessi, J. Gallay, and I.J. Schalk. (2007). Identification of residues of FpvA involved in the different steps of Pvd-Fe uptake in Pseudomonas aeruginosa. Biochemistry 46: 11707-11717.

Nau, C.D. and J. Konisky. (1989). Evolutionary relationship between the TonB-dependent outer membrane transport proteins: nucleotide and amino-acid sequences of the Escherichia coli colicin I receptor gene. J. Bacteriol. 171: 1041-1047.

Oakhill, J.S., B.J. Sutton, A.R. Gorringe, and R.W. Evans. (2005). Homology modelling of transferrin-binding protein A from Neisseria meningitidis. Protein Eng Des Sel 18: 221-228.

Obando S, T.A., M.M. Babykin, and V.V. Zinchenko. (2018). A Cluster of Five Genes Essential for the Utilization of Dihydroxamate Xenosiderophores in Synechocystis sp. PCC 6803. Curr. Microbiol. [Epub: Ahead of Print]

Oke, M., R. Sarra, R. Ghirlando, S. Farnaud, A.R. Gorringe, R.W. Evans, and S.K. Buchanan. (2004). The plug domain of a neisserial TonB-dependent transporter retains structural integrity in the absence of its transmembrane β-barrel. FEBS Lett. 564: 294-300.

Olczak T., A. Sroka, J. Potempa, M. Olczak. (2007). Porphyromonas gingivalis HmuY and HmuR: further characterization of a novel mechanism of heme utilization. Arch Microbiol.

Olczak, T., D.W. Dixon, and C.A. Genco. (2001). Binding specificity of the Porphyromonas gingivalis heme and hemoglobin receptor HmuR, gingipain K, and gingipain R1 for heme, porphyrins, and metalloporphyrins. J. Bacteriol. 183: 5599-5608.

Passmore, I.J., J.M. Dow, F. Coll, J. Cuccui, T. Palmer, and B.W. Wren. (2020). The ferric citrate regulator, FecR, is translocated across the bacterial inner membrane a unique Twin-arginine transport dependent mechanism. J. Bacteriol. [Epub: Ahead of Print]

Patzer, S.I., M.R. Baquero, D. Bravo, F. Moreno, and K. Hantke. (2003). The colicin G, H and X determinants encode microcins M and H47, which might utilize the catecholate siderophore receptors FepA, Cir, Fiu and IroN. Microbiology 149: 2557-2570.

Pawelek, P.D., N. Croteau, C. Ng-Thow-Hing, C.M. Khursigara, N. Moiseeva, M. Allaire, and J.W. Coulton. (2006). Structure of TonB in complex with FhuA, E. coli outer membrane receptor. Science 312: 1399-1402.

Postle, K. (1993). TonB protein and energy transduction between membranes. J. Bioenerg. Biomembr. 25: 591-601.

Postle, K. and R.J. Kadner. (2003). Touch and go: tying TonB to transport. Mol. Microbiol. 49: 869-882.

Prinz, T., M. Meyer, A. Pettersson, and J. Tommassen. (1999). Structural characterization of the lactoferrin receptor from Neisseria meningitidis. J. Bacteriol. 181: 4417-4419.

Qiu, G.W., W.J. Lou, C.Y. Sun, N. Yang, Z.K. Li, D.L. Li, S.S. Zang, F.X. Fu, D.A. Hutchins, H.B. Jiang, and B.S. Qiu. (2018). Outer Membrane Iron Uptake Pathways in the Model Cyanobacterium Synechocystis sp. Strain PCC 6803. Appl. Environ. Microbiol. 84:.

Rabsch, W., W. Voight, R. Reissbrodt, R.M. Tsolis, and A.J. Bäumler. (1999). Salmonella typhimurium IroN and FepA proteins mediate uptake of enterobactin but differ in their specificity for other siderophores. J. Bacteriol. 181: 3610-3612.

Reeves, A.R., G.R. Wang, and A.A. Salyers. (1997). Characterization of four outer membrane proteins that play a role in utilization of starch by Bacteroides thetaiotaomicron. J. Bacteriol. 179: 643-649.

Rodionov, D.A., A.G. Vitreschak, A.A. Mironov, and M.S. Gelfand. (2002). Comparative genomics of thiamin biosynthesis in procaryotes. New genes and regulatory mechanisms. J. Biol. Chem. 277: 48949-48959.

Romagnoli, S., F. Agriesti, and V. Scarlato. (2011). In vivo recognition of the fecA3 target promoter by Helicobacter pylori NikR. J. Bacteriol. 193: 1131-1141.

Samsonov, V.V., V.V. Samsonov, and S.P. Sineoky. (2002). DcrA and dcrB Escherichia coli genes can control DNA injection by phages specific for BtuB and FhuA receptors. Res. Microbiol. 153: 639-646.

Schalk IJ., Lamont IL. and Cobessi D. (2009). Structure-function relationships in the bifunctional ferrisiderophore FpvA receptor from Pseudomonas aeruginosa. Biometals. 22(4):671-8.

Schauer, K., B. Gouget, M. Carrière, A. Labigne, and H. de Reuse. (2007). Novel nickel transport mechanism across the bacterial outer membrane energized by the TonB/ExbB/ExbD machinery. Mol. Microbiol. 63: 1054-1068.

Schryvers, A.B. and I. Stojiljkovic. (1999). Iron acquisition systems in the pathogenic Neisseria. Mol. Microbiol. 32: 1117-1123.

Shipman, J.A., J.E. Berleman, and A.A. Salyers. (2000). Characterization of four outer membrane proteins involved in binding starch to the cell surface of Bacteroides thetaiotaomicron. J. Bacteriol. 182: 5365-5372.

Shipman, J.A., K.H. Cho, H.A. Siegel, and A.A. Salyers. (1999). Physiological characterization of SusG, an outer membrane protein essential for starch utilization by Bacteroides thetaiotaomicron. J. Bacteriol. 181: 7206-7211.

Shultis, D.D., M.D. Purdy, C.N. Banchs, and M.C. Wiener. (2006). Outer membrane active transport: structure of the BtuB:TonB complex. Science 312: 1396-1399.

Sikora, A., B. Joseph, M. Matson, J.R. Staley, and D.S. Cafiso. (2016). Allosteric Signaling Is Bidirectional in an Outer-Membrane Transport Protein. Biophys. J. 111: 1908-1918.

Slakeski, N., S.G. Dashper, P. Cook, C. Poon, C. Moore, and E.C. Reynolds. (2000). A Porphyromonas gingivalis genetic locus encoding a heme transport system. Oral Microbiol Immunol 15: 388-392.

Smajs, D. and G.M. Weinstock. (2001). The iron- and temperature-regulated cjrBC genes of Shigella and enteroinvasive Escherichia coli strains code for colicin Js uptake. J. Bacteriol. 183: 3958-3966.

Udho, E., K.S. Jakes, S.K. Buchanan, K.J. James, X. Jiang, P.E. Klebba, and A. Finkelstein. (2009). Reconstitution of bacterial outer membrane TonB-dependent transporters in planar lipid bilayer membranes. Proc. Natl. Acad. Sci. USA 106: 21990-21995.

van Vliet, A.H., J. Stoof, R. Vlasblom, S.A. Wainwright, N.J. Hughes, D.J. Kelly, S. Bereswill, J.J. Bijlsma, T. Hoogenboezem, C.M. Vandenbroucke-Grauls, M. Kist, E.J. Kuipers, and J.G. Kusters. (2002). The role of the Ferric Uptake Regulator (Fur) in regulation of Helicobacter pylori iron uptake. Helicobacter 7: 237-244.

Vanderpool, C.K. and S.K. Armstrong. (2004). Integration of environmental signals controls expression of Bordetella heme utilization genes. J. Bacteriol. 186: 938-948.

Vassen, V., C. Valotteau, C. Feuillie, C. Formosa-Dague, Y.F. Dufrêne, and X. De Bolle. (2019). Localized incorporation of outer membrane components in the pathogen. EMBO. J. 38:.

Vianney, A., T.M. Lewin, W.F. Beyer, Jr., J.C. Lazzaroni, R. Portalier, and R.E. Webster. (1994). Membrane topology and mutational analysis of the TolQ protein of Escherichia coli required for the uptake of macromolecules and cell envelope integrity. J. Bacteriol. 176: 822-829.

Wei, X., L.A. Sayavedra-Soto, and D.J. Arp. (2007). Characterization of the ferrioxamine uptake system of Nitrosomonas europaea. Microbiology. 153: 3963-3972.

Wexler, H.M., E.K. Read, and T.J. Tomzynski. (2002). Characterization of omp200, a porin gene complex from Bacteroides fragilis: omp121 and omp71, gene sequence, deduced amino acid sequences and predictions of porin structure. Gene 283: 95-105.

Wojtowicz, H., A. Prochnicka-Chalufour, G. Cardoso de Amorim, O. Roudenko, C. Simenel, I. Malki, G. Pehau-Arnaudet, F. Gubellini, A. Koutsioubas, J. Perez, P. Delepelaire, M. Delepierre, R. Fronzes, and N. Izadi-Pruneyre. (2016). Structural basis of the signaling through a bacterial membrane receptor HasR deciphered by an integrative approach. Biochem. J. [Epub: Ahead of Print]

Wolfe AJ., Mohammad MM., Thakur AK. and Movileanu L. (2016). Global redesign of a native beta-barrel scaffold. Biochim Biophys Acta. 1858(1):19-29.

Wolff, N., N. Izadi-Pruneyre, J. Couprie, M. Habeck, J. Linge, W. Rieping, C. Wandersman, M. Nilges, M. Delepierre, and A. Lecroisey. (2008). Comparative analysis of structural and dynamic properties of the loaded and unloaded hemophore HasA: functional implications. J Mol Biol 376: 517-25.

Wyckoff, E.E., B.E. Allred, K.N. Raymond, and S.M. Payne. (2015). Catechol Siderophore Transport by Vibrio cholerae. J. Bacteriol. 197: 2840-2849.

Xiong, K., Z. Chen, C. Zhu, J. Li, X. Hu, X. Rao, and Y. Cong. (2015). Safety and immunogenicity of an attenuated Salmonella enterica serovar Paratyphi A vaccine candidate. Int. J. Med. Microbiol. 305: 563-571.

Xiong, K., Z. Chen, G. Xiang, J. Wang, X. Rao, F. Hu, and Y. Cong. (2012). Deletion of yncD gene in Salmonella enterica ssp. enterica serovar Typhi leads to attenuation in mouse model. FEMS Microbiol. Lett. 328: 70-77.

Yang, J.N., C. Wang, C. Guo, X.X. Peng, and H. Li. (2011). Outer membrane proteome and its regulation networks in response to glucose concentration changes in Escherichia coli. Mol Biosyst 7: 3087-3093.

Ye, L., S. Matthijs, J. Bodilis, F. Hildebrand, J. Raes, and P. Cornelis. (2014). Analysis of the draft genome of Pseudomonas fluorescens ATCC17400 indicates a capacity to take up iron from a wide range of sources, including different exogenous pyoverdines. Biometals 27: 633-644.

Yoneyama, H. and T. Nakae. (1996). Protein C (OprC) of the outer membrane of Pseudomonas aeruginosa is a copper-regulated channel protein. Microbiology 142(Pt8): 2137-2144.

Zhu, Y., K.J. Kwiatkowski, T. Yang, S.S. Kharade, C.M. Bahr, N.M. Koropatkin, W. Liu, and M.J. McBride. (2015). Outer membrane proteins related to SusC and SusD are not required for Cytophaga hutchinsonii cellulose utilization. Appl. Microbiol. Biotechnol. 99: 6339-6350.


TC#NameOrganismal TypeExample

FhuE ferric-coprogen receptor of 729 aas and 1 N-terminal TMS.  It is required for the uptake of Fe3+ via coprogen, ferrioxamine B, and rhodotorulic acid (Hantke 1983). The crystal structure of FhuE in complex with coprogen was determined, providing a structural basis to explain its selective promiscuity (Grinter and Lithgow 2019). The structural data, in combination with functional analysis, showed that FhuE has evolved to specifically engage with planar siderophores. A potential evolutionary driver, and a critical consequence of this selectivity, is that it allows FhuE to exclude antibiotics that mimic nonplanar hydroxamate siderophores.  These toxic molecules could otherwise cross the outer membrane barrier through a Trojan horse mechanism (Grinter and Lithgow 2019).

Gram-negative bacteria

FhuE of E. coli

1.B.14.1.10The outer membrane ferrioxamine/desferrioxamine receptor, FoxA(1) (most like TC# 1.B.14.1.4 and 9) (Wei et al., 2007)BacteriaFoxA(1) of Nitrosomonas europaea (Q82VI7)
1.B.14.1.11The outer membrane ferric-anguibactin receptor/transporter, FatA (Lopez and Crosa, 2007)BacteriaFatA of Vibrio anguillarum (P11461)
1.B.14.1.12FecA ferric-citrate receptor (PA3901) (Marshall et al., 2009) (62% identical to the E. coli FecA).

Gram-negative bacteria

FecA of Pseudomonas aeruginosa (Q9HXB2)

1.B.14.1.13CfrA ferric receptor (Carswell et al., 2008).

Gram-negative bacteria

CfrA of Campylobacter jejuni (A3ZKG8)

1.B.14.1.14Ferric-pseudobactin 358 receptorBacteria

PupA of Pseudomonas putida

1.B.14.1.15Ferrichrome receptor FcuABacteriaFcuA of Yersinia enterocolitica
1.B.14.1.16Probable TonB-dependent receptor BfrD (Virulence-associated outer membrane protein Vir-90)BacteriaBfrD of Bordetella pertussis

Ferrioxamine receptor, FoxA.  Transports a variety of Ferrioxamine B analogues (Kornreich-Leshem et al. 2005).


FoxA of Yersinia enterocolitica


TonB-dependent receptor (Bhat et al. 2011).


TonB-dependent receptor of Myxococcus xanthus


TonB-dependent receptor


TonB-dependent receptor of Myxococcus xanthus


FhuA ferrichrome (also albomycin and rifamycin; Colicin M; Microcin J25; Phage T5) receptor (transports phage T1, T5 and φ80 DNA across the outer membrane, dependent on DcrA (SdaC; TC #2.A.42.2.1) and DcrB) (Forms a complex with and acts with TonB and FhuD (the periplasmic binding receptor (3.A.1.14.3) to deliver siderophore to FhuD (Carter et al., 2006; Braun et al., 2009)).  Deletion of the 160-residue cork domain and five large extracellular loops converted this non-conductive, monomeric, 22-stranded beta-barrel protein into a large-conductance protein pore (Wolfe et al. 2015).

Gram-negative bacteria

FhuA of E. coli


The iron-citrate receptor/transporter, FecA.  TonB mediates both signaling and transport by unfolding portions of the transporter (Mokdad et al. 2012). The ferric citrate regulator, FecR, is translocated across the bacterial inner membrane via a unique Twin-arginine transport dependent mechanism (Passmore et al. 2020).


FecA of E. coli


Ferrioxamine receptor


Ferrioxamine receptor of Pseudovibrio sp. JE062


FepA ferri-enterobactin (also Colicins B and D) receptor for the 37 aas disulfide-containing K+ channel toxin, BgK (Braud et al., 2004). Functions by a "ball and chain" mechanism; The transport process involves expulsion of the N-terminal globular domain from the C-terminal beta-barrel (Ma et al. 2007). Conformational rearrangements occur in the N-terminus of FepA during FeEnt transport, but disengagement of the N-domain, out of the rigid channel suggests that it remains within the transmembrane pore as FeEnt enters the periplasm (Majumdar et al. 2020).

Gram-negative bacteria

FepA of E. coli


OMR of 938 aas


OMR of Myxococcus xanthus


Putative TonB-dependent siderophore receptor, Sde_3611


Sde3611 of Saccharophagus degradans


Nickel uptake receptor/channel of 724 aas (Benoit et al. 2013).


HH0418 of Helicobacter hepaticus


Iron siderophore (ferripyoverdine) receptor and importer, FpvA of 808 aas (Ye et al. 2014). The crystal structure of FpvA has been solved at 3.6 Å resolution. It is folded in two domains: a transmembrane 22-stranded beta-barrel domain occluded by an N-terminal domain containing a mixed four-stranded beta-sheet (the plug). The beta-strands of the barrel are connected by long extracellular loops and short periplasmic turns (Cobessi et al. 2005).


FpvA of Pseudomonas aeruginosa


Iron(III) dicitrate transport protein, FecA1: iron dicitrate uptake receptor of 767 aas.  Regulated by the ferric uptake regulator transcription factor, Fur (van Vliet et al. 2002) in response to iron availability (Danielli et al. 2009). Involved in iron deficiency anemia in children (Kato et al. 2017).

FecA1 of Helicobacter pylori


FecA3 of 843 aas.  Probable receptor for nickel.  Shows 50% identiy with TC# 1.B.14.1.27. Repressed by nickel in the medium, mediated by NikR (Danielli et al. 2009). NikR seems to interact in an asymmetric mode with the fecA3 target to repress its transcription (Romagnoli et al. 2011).

FecA3 of Helicobacter pylori


Iron-deficiency-induced (2x) iron siderophore uptake outer membrane receptor, FhuA, of 828 aas and 1 N-terminal TMS (Qiu et al. 2018). 

FhuA of Synechocystis sp. (strain PCC 6803 / Kazusa)


Ferric enterobactin (also ferricorynebactin) receptor, IroN

Gram-negative bacteria

IroN of Salmonella typhimurium


Outer membrand iron siderophore uptake receptor of 853 aas and 1 N-terminal TMS, Slr1490.

Slr1490 of Synechocystis sp. (strain PCC 6803 / Kazusa)


Outer membrane porin, PiuA, of 753 aas.  A deficiency of this iron transporter, PiuA in P. aeruginosa, caused 16-fold increases in cefiderocol resistance, suggesting that it contribute to the permeation of cefiderocol into the cell (Ito et al. 2018).

PiuA of Pseudomonas aeruginosa


Catechol iron-siderophore uptake system, IrgA, an iron-regulated outer membrane virulence protein, of 652 aas and 1 N-terminal TMS (Wyckoff et al. 2015). It is involved in the initial step of iron uptake by binding ferric vibriobactin, an iron chelatin siderophore that allows V. cholerae to extract iron from the environment and takes up linear enterobactin derivatives (Wyckoff et al. 2015).

IrgA of Vibrio cholerae


Heme/hemin outer membrane TonB-related receptor of 708 aas, Tlr (Slakeski et al. 2000).

Tlr of Porphyromonas gingivalis


CirA Fe3+-catecholate receptor. Serves as the receptor for the TonB- and proton-dependent uptake of the E. coli bacteriocin, Microcin L (MccL) (Morin et al., 2011). CirA is also the translocator for colicin Ia (Jakes and Finkelstein, 2010). Plays roles in cefiderocol and ceftazidime resistance (Ito et al. 2018).

Gram-negative bacteria

CirA of E. coli

1.B.14.1.5PfeA ferric enterobactin receptor Gram-negative bacteria PfeA of Pseudomonas aeruginosa

Ferripyoverdine/pyocin S3 receptor, FpvA (Adams et al., 2006; Nader et al., 2007; Schalk et al., 2009Nader et al., 2011)

Gram-negative bacteria

FpvA of Pseudomonas aeruginosa

1.B.14.1.7Iron malleobactin receptor, FmtA (Alice et al., 2006)Gram-negative bacteriaFmtA of Burkholderia pseudomallei (EBA51007)

The Ferripyochelin receptor, FptA (Michel et al., 2007). In addition to Fe3+, FptA takes up Co2+, Ga3+, and Ni2+ at low rates (Braud et al., 2009). The high resolution 3-d structure of FptA (2.0 Å) bound to iron-pyochelin has been solved (Cobessi et al. 2005). The pyochelin molecule provides atetra-dentate coordination of iron. The structure is typical of the TonB-dependent receptor/transporter superfamily.

Gram-negative bacteria

FptA of Pseudomonas aeruginosa (P42512)


Ferric-catecholate siderophore (dihydroxybenzoylserine, dihydroxybenzoate) uptake receptor, Fiu or YbiL (Hantke, 1990; Curtis et al., 1988). Plays roles in cefiderocol and ceftazidime resistance (Ito et al. 2018). It can also transport catechol-substituted cephalosporins and is a receptor for microcins M, H47 and E492 (Patzer et al. 2003; Destoumieux-Garzón et al. 2006).

Gram-negative bacteria

Fiu of E. coli (P75780)


TC#NameOrganismal TypeExample
1.B.14.10.1Heme/hemoglobin receptor, HmuR (also binds the Cu2+, Zn2+ and Fe2+ derivatives of protoporphyrin IX). Functions with the O.M. heme binding lipoprotein, HmuY (AAQ66587; Olczak et al., 2007).Gram-negative bacteriaHmuR of Porphyromonas gingivalis

TonB-dependent receptor


TonB receptor of Myxococcus xanthus


TonB-dependent receptor


TonB recpetor of Myxocuccus xanthus


Putative TonB-dependent receptor


OMR of Gloeobacter violaceus


Probable TonB-dependent long chain alkane receptor of 699 aas (Gregson et al. 2018).

TonB-dependent receptor of Thalassolituus oleivorans


TC#NameOrganismal TypeExample

The Nickel (Ni2+) receptor (FrpB4; Hp1512) of 877 aas. Energized by the TonB/ExbBD complex (Schauer et al., 2007). Capable of binding both haem and haemoglobin but shows greater affinity for haem. The mRNA levels of frpB1 were repressed by iron and lightly modulated by haem or haemoglobin. Overexpression of the frpB1 gene supported cellular growth when haem or haemoglobin were supplied as the only iron source (Carrizo-Chávez et al. 2012).

Gram-negative bacteria

FrpB4 of Helicobacter pylori (Q9ZJA8)


TC#NameOrganismal TypeExample
1.B.14.12.1The TonB-dependent maltooligosaccharide OM receptor/porin, MalA (Lohmiller et al., 2008).BacteriaMalA of Caulobacter crescentus (Q9A608)
1.B.14.12.2The N-acetyl glucosamine/chitin oligosaccharide OM receptor porin, NagA (Eisenbeis et al., 2008).BacteriaNagA of Caulobacter crescentus (Q9AAZ6)

TonB-dependent receptor


TonB-dependent receptor of Myxococcus xanthus


TC#NameOrganismal TypeExample

TonB-dependent receptor of 763 aas


Receptor of Xanthomonas campestris


TC#NameOrganismal TypeExample

The thiamine receptor (BT2390) (energized by TonB/ExbBD) (Rodionov et al. 2002).


BT2390 of Bacteroides thetaiotaomicron (Q8A552)


TC#NameOrganismal TypeExample

Putative porin of the DUF4289 family; 655 aas and 32 putative transmembrane beta strands.


PP of Psychroflexus torquis


Putative porin of 776 aas


PP of Provotella ruminicola


Putative porin of 631 aas


PP of Amoebophilus asiaticus


Putative DUF4289 family porin of 687 aas


PP of Niastella koreensis


Putative porin of 627 aas


PP of Melioribacter roseus


Putative porin of 650 aas


PP of Ignavibacterium album


Putative porin of 621 aas


PP of Cryptocercus punctulatus


TC#NameOrganismal TypeExample

DUF940 homologue of 720 aas, one signal sequence and 30 putative β-strands.  Homologous to proteins designated YmcA, WbfB and YjbH.


DUF940 homologue of Protochlamydia amoebophila


Putative LPS exporter receptor, OtuG.  It's gene is in a cluster with several LPS biosynthetic enzymes.


OtuG of Vibrio parahaemolyticus


OMR of 698 aas and 1 N-terminal TMS, GlfD or YmcA.  Probably involved in capsular polysaccharide export (Peleg et al. 2005).

GlfD of E. coli


DUF940 homologue of 953 aas, one N-terminal signal sequence and 30 putative beta strands.


DUF940 homologue of Chromobacterium violaceum


DUF940 homologue of 689 aas, one N-terminal signal sequence and 28 putative TM β-strands.


DUF940 homologue of Psychromonas ingrahamii


DUF940 homologue of 940 aas, one N-terminal signal sequence and 32 putative TM β-strands.


DUF940 homologue of E. coli


DUF940 homologue of 716 aas with one N-terminal signal sequence and 27 putative beta strands.


DUF940 homologue of Parachlamydia acanthamoebae


DUF940 homologue of 718 aas, an N-terminal signal sequence and 33 putative beta strands.


DUF940 homologue of Photobacterium angustum


Putative polysaccharide exporter of 690 aas and 34 predicted TMSs, WbfB.  Encoded in a gene cluster with polysaccharide biosynthetic enzymes and a putative periplasmic polysaccharide export protein.


Putative OMR concerned with polysaccharide export of Syntrophus aciditrophicus


Putative polysaccharide/glycolipid/glycoprotein export receptor of 736 aas and 30 predicted β-strands, WbfB.  The gene encoding this protein is in a cluster with UDP-N-acetyl D-quinovosamine -4 epimerase.


Putative exporter of Vibrio anguillarum


Putative lipopolysaccharide export receptor, WbfB.  It is encoded in a gene cluster with LPS biosynthetic genes.


WbfB of Vibrio parahaemolyticus


TC#NameOrganismal TypeExample

Uncharacterized protein of 922 aas


UP of Dyadobacter fermentans


Putative Planctomycetes OMR of 799 aas


Putative OMR of Planctomyces brasiliensis


Putative Planctomycetes OMR of 1101 aas


Putative OMR of Isosphaera pallida


Uncharacterized protein of 1055 aas


UP of Lentisphaera araneosa


TC#NameOrganismal TypeExample

Putative Verucomicrobial OMP of 676 aas 


Putative OMR of Optutus terrae


Uncharacterized OM channel superfamily member of 791 aas


UP of Pedosphaera parvula


TC#NameOrganismal TypeExample

Putative TonB-dpenedent receptor of 790 aas, YddB.  It is encoded by a gene adjacent to the YddA-encoding gene (TC# 3.A.1.203.11). YddA is a probable fatty acid exporter.  the yddB gene is adjacent to a gene encoding a putative Zn2+ protease, PqqL.

YddB of E. coli


TonB-dependent receptor of 843 aas.

Receptor of Rhodobacter capsulatus


TonB-dependent receptor/transporter of 834 aas.

Receptor of Verrucomicrobiaceae bacterium


TC#NameOrganismal TypeExample

HmbR Hemoglobin receptor

Gram-negative bacteria HmbR of Neisseria meningitidis
1.B.14.2.10Heme transporter BhuA (Brucella heme uptake protein A)Bacteria

BhuA of Brucella abortus

1.B.14.2.11Heme/hemopexin utilization protein CBacteriaHxuC of Haemophilus influenzae

The transferrin receptor/lipoprotein complex, TbpAB (TbpA receptor, 912aas; TbpB lipoprotein, 625aas). The plug domain can fold independently of the beta-barrel, but extracellular loops of the beta-barrel are required for ferritin binding (Oke et al. 2004).


TbpAB of Haemophilus influenzae
TbpA (P44970)
TbpB (P44971)


Hemoglobin receptor, HgbA.  Residues for hemoglobin binding and utilization differ (Fusco et al. 2013).


HgbA of Haemophilus ducreyi


Heme/hemoglobin receptor of 660 aas and 22 C-terminal β-strands with an N-terminal "plug" domain, ShuA.  The 3-d structure is known to 2.6 Å resolution, revealing the histidyl residues in the barrel and plug that can interact with heme (Cobessi et al. 2010).


ShuA of Shigella dysenteriae

Uncharacterized outer membrane receptor, probably for iron transport.


OMR of Xanthomonas oryzae

Transferrin binding protein A, TbpA of 914 aas. A 3-D model revealed a narrow channel through the entire length of the protein. The spatial arrangement of external loops, and their relevance to the mechanism of iron translocation is presented (Oakhill et al. 2005).

TbpA of Neisseria meningitidis


The iron-catechol siderophore uptake/receptor, VctA, of 659 aas.  Linear enterobactin derivatives are substrates, but it also transports the synthetic siderophore MECAM [1,3,5-N,N',N″-tris-(2,3-dihydroxybenzoyl)-triaminomethylbenzene] (Wyckoff et al. 2015).

VctA of Virbio cholerae

1.B.14.2.2HemR Heme (Hemin) receptor Gram-negative bacteria HemR of Yersinia enterocolitica
1.B.14.2.3HpuAB hemoglobin-haptoglobin receptor; porphyrin transporter (HpuA=lipoprotein; HpuB=OMR porin) Gram-negative bacteria HpuAB of Neisseria meningitidis

Lactoferrin receptor (A=OMR porin; B=lipoprotein), LbpAB or IroAB. This two-component system extracts iron from the host glycoproteins lactoferrin and transferrin. Homologous iron-transport systems consist of a membrane-bound transporter and an accessory lipoprotein. The crystal structure of the N-terminal domain (N-lobe) of the accessory lipoprotein, lactoferrin-binding protein B (LbpB) is homologous to the structures of the accessory lipoproteins, transferrin-binding protein B (TbpB) and LbpB from the bovine pathogen Moraxella bovis. Docking the LbpB  with lactoferrin reveals extensive binding interactions with the N1 subdomain of lactoferrin. The nature of the interaction precludes apolactoferrin from binding LbpB, ensuring the specificity for iron-loaded lactoferrin, safeguarding proper delivery of iron-bound lactoferrin to the transporter LbpA. The structure also reveals a possible secondary role for LbpB in protecting the bacteria from host defences. Following proteolytic digestion of lactoferrin, a cationic peptide derived from the N-terminus is released. This peptide, called lactoferricin, exhibits potent antimicrobial effects. The docked model of LbpB with lactoferrin reveals that LbpB interacts extensively with the N-terminal lactoferricin region (Brooks et al. 2014). 

Gram-negative bacteria

LbpAB of Neisseria meningitidis

1.B.14.2.5TbpA single component transferrin receptor Gram-negative bacteria TbpA of Pasteurella multocida
1.B.14.2.6HugA heme receptor/porin

Gram-negative bacteria

HugA of Plesiomonas shigelloides (Q93SS7)


Hemin (Heme)-binding receptor, ShmR (also transports the toxic heme analog, gallium protoporphyrin) (Amarelle et al., 2008).


ShmR of Sinorhizobium meliloti (Q92N43)


The heme-iron (from hemin and hemoglobin) utilization receptor, BhuR (Brickman et al., 2006; Vanderpool and Armstrong, 2004).

Gram-negative bacteria

BhuR of Bordetella pertussis (Q7VSQ4)

1.B.14.2.9Probable TonB-dependent receptor NMB0964Y964 of Neisseria meningitidis MC58

TC#NameOrganismal TypeExample

BtuB cobalamin receptor (also transports phage C1 DNA across the outer membrane). Two Ca2+ binding sites in BtuB mediate cobalamine binding (Cadieux et al., 2007). Cobalamine uptake into the periplasm is reversible, but efflux is pmf-independent (Cadieux et al., 2007). The 3-d structure is available (PDB#1NQE).  The Ton box and the extracellular substrate binding site are allosterically coupled (bidirectional), and TonB binding may initiate a partial round of transport (Sikora et al. 2016).  Substrate binding to the extracellular surface of the protein triggers the unfolding of an energy coupling motif at the periplasmic surface.  Thus, substrate binding reduces the interaction free energy between certain residues, thereby triggering the unfolding of the energy coupling motif (Lukasik et al. 2007). Multiple extracellular loops contribute to substrate binding and transport by BtuB (Fuller-Schaefer and Kadner 2005).

Gram-negative bacteria

BtuB of E. coli


TonB-dependent receptor (Bhat et al. 2011).


TonB-dependent receptor of Myxococcus xanthus


TonB-dependent receptor (Bhat et al. 2011).


TonB receptor of Myxococcus xanthus


TonB-dependent receptor (Bhat et al. 2011).


TonB-dependent receptor of Myxococcus xanthus


TonB-dependent receptor (Bhat et al. 2011).


TonB-dependent receptor of Myxococcus xanthus


Probable siderophore-specific outer membrane receptor of 869 aas, MxcH


MxcH of Stigmatella aurantiaca


TonB-dependent receptor


OMR of Shewanella oneidensis


TC#NameOrganismal TypeExample

Cu2+-transporting, Cu2+-regulated outer membrane protein C, OprC (Yoneyama and Nakae 1996). OprC impairs host defense by increasing the quorum-sensing-mediated virulence of P. aeruginosa (Gao et al. 2020).

Gram-negative bacteria

OprC of Pseudomonas aeruginosa

1.B.14.4.2Cu2+-transporting, outer membrane protein, NosA Gram-negative bacteria NosA of Pseudomonas stutzeri

TonB-dependent receptor/channel for substrate uptake across the outer membrane of 656 aas

Receptor of E. coli


TC#NameOrganismal TypeExample

HasR receptor-HasA haemophore heme receptor complex (HasA, an extracellular heme binding protein, binds one heme and transfers it directly to HasR, which uses HasB (2.C.1.1.2) (a TonB homologue) instead of TonB (2.C.1.1.1) for energization) (Benevides-Matos et al., 2008; Izadi-Pruneyre et al., 2006; Lefèvre et al., 2008; Benevides-Matos and Biville, 2010). A signaling domain in HasR interacts with a partially unfolded periplasmic domain of an antisigma factor, HasS, to control transcription by an ECF sigma factor (Malki et al. 2014).  The HasR domain responsible for signal transfer is highly flexible in two stages of signaling, extends into the periplasm at about 70 to 90 A from the HasR beta-barrel and exhibits local conformational changes in response to the arrival of signaling activators (Wojtowicz et al. 2016).

Gram-negative bacteria

HasR-HasA of Serratia marcescens


The heme receptor HxuC (PA1302) serves as a pyocin M4 (Colicin M-type; PaeM4) target at the cellular surface.

HxuC of Pseudomonas aeruginosa


TC#NameOrganismal TypeExample

SusC receptor/porin for maltooligosaccharides (up to maltoheptaose). Forms a complex with and functions with SusD porin (TC# 8.A.46.1.1) as well as SusE and SusF porins (TC#s 1.B.38.1.1 and 1.2) as well as the SusG α-amylase (TC#8.A.9.1.3).  These proteins are all involved in starch utilization (Shipman et al. 2000; Reeves et al. 1997; Cho and Salyers 2001; Foley et al. 2018).

Gram-negative bacteria

SusC of Bacteroides thetaiotaomicron


DUF4480 putative OMR of 835 aas.


OMR of Capnocytophaga canimorsus


OMR (DUF4480) of 976 aas


OMR of Zobellia galactanivorans


OMR (DUF4480) of 775 aas


OMR of Saprospira grandis


SusC homologue of 940 aas.  Functions with SusD homolgoue TC# 8.A.46.1.2.  


SusC homologue of Bacteroides thetaiotaomicron


Putative porin of 830 aas and 16 predicted TMSs.  The β-barrel domain is the N-terminal ~250 aas which corresponds to the DUF4480 or Peptidase M14NE family in Pfam.  The large hydrophilic C-terminal domain is of unknown function.


Putative porin of Aequorivita sublithincola


TonB-dependent collagenase (proteinase) of 1047 aas (Bhattacharya et al. 2017).  The primary pathogen of the Great Barrier Reef sponge, Rhopaloeides odorabile, identified as a unique strain (NW4327) of Pseudoalteromonas agarivorans. It produces collagenases which degrade R. odorabile skeletal fibers.

Collagenase of Pseudoalteromonas agarivolans NW4327 (a marine sponge parasite)


Possible Iron receptor, RagA of 1036 aas.  Its gene forms part of a small operon which may have arisen via horizontal gene transfer into the genome. The 55 kDa antigen (RagB; TC# 8.A.46.3.5), encoded within the same operon, may act in concert at the surface of the bacterium to facilitate active transport, mediated through the periplasmic spanning protein, TonB (Curtis et al. 1999).

RagAB of Porphyromonas gingivalis


SusC of 1041 aas and 1 N-terminal TMS (Joglekar et al. 2018).

SusC of Bacteroides thetaiotaomicron


TonB-dependent receptor/transporter of 909 aas

Receptor of Granulicella mallensis

1.B.14.6.2The Omp200 porin complex (consists of Omp121 [an OMR family member] and Omp71 [a protein nonhomologous to other proteins in the databases])Gram-negative bacteriaOmp121/Omp71 complex of Bacteroides fragilis

Outer membrane porin required for intercellular signalling via C-signal (CsgA), Oar (Bhat et al. 2011).


Oar of Myxococcus xanthus


TonB-dependent outer membrane porin/receptor, Oar


Oar of Stenotrophomonas maltophila


TonB-dependent outer membrane receptor of 792 aas.


TonB receptor of Bacteroides caccae


TonB-dependent receptor of 970 aas


TonB receptor of Leptospira interrogans


TonB-dependent receptor


TonB receptor of Pedobacter heparinus


Putative OMR (DUF4480) of 709 aas and one N-terminal TMS.  The first 120 residues show sequence similarity with TC#1.B.14.6.2.


Putative OMR of Bacteroides fragilis


Putative OMR (DUF4480) of 828 aas, and N-terminal TMS and 32 predicted TM β-strands.


Putative OMR of Croceibacter atlanticus


TC#NameOrganismal TypeExample

CjrC outer membrane receptor of 753 aas.  It is iron and temperature regulated, and functions with CjrB, a distant TonB homologue (TC# 2.C.1.1.3).  Together these two proteins are required for uptake of colicin J in Shigella and enteroinvasive E. coli strains (Smajs and Weinstock 2001).


CjrC of E. coli


Probable TonB-dependent receptor NMB1497


NMB1497 of Neisseria meningitidis 


Probable TonB-dependent receptor HI_1217


HI_1217 of Haemophilus influenzae


TC#NameOrganismal TypeExample
1.B.14.8.1Putative salicin/arbutin (aromatic β-glucoside) receptor, SalC Gram-negative bacteria SalC of Azospirillum irakense
1.B.14.8.2The iron (Fe3+) · pyridine-2,6-bis(thiocarboxylic acid) (PDTC) receptor, PdtK. Functions with the MFS carrier, PdtE (TC #2.A.1.55.1) (Leach and Lewis, 2006).Gram-negative bacteriaPdtK of Pseudomonas putida (ABC68350)

Vibriobactin receptor, VuiA or VuuA of 687 aas and 1 N-terminal TMS. There is conserved, global coordinate iron regulation in V. cholerae by the Fur transcription factor, responsive to iron (Butterton et al. 1992). V. cholerae synthesizes and uses the catechol siderophore vibriobactin and also uses siderophores secreted by other species, including enterobactin produced by E. coli (Wyckoff et al. 2015).  ViuB, a putative V. cholerae siderophore-interacting protein (SIP), functionally substituted for the E. coli ferric reductase YqjH, which promotes the release of iron from the siderophore in the bacterial cytoplasm. In V. cholerae, ViuB is required for the use of vibriobactin but is not required for the use of MECAM, fluvibactin, ferrichrome, or the linear derivatives of enterobactin, all substrates of ViuA (Wyckoff et al. 2015).


ViuA of Vibrio cholerae serotype O1


The thiamine receptor (SO2715) (energized by TonB/ExbBD) (Rodionov et al. 2002)


SO2715 of Shewanella oneidensis (Q8EDM8)


TonB-dependent receptor of 726 aas.


Receptor of Colwellia psychrerythraea


The (thio)quinolobactin receptor, QbsI, of 669 aa


QbsI of Pseudomonas fluorescens


FyuA Fe3+-yersiniabactin and pesticin (Psn; a bacteriocin) receptor and uptake protein of 673 aas. It contributes to biofilm formation and infection (Hancock et al., 2008).

Gram-negative bacteria

FyuA of Yersinia enterocolitica (P0C2M9)


TC#NameOrganismal TypeExample
1.B.14.9.1RhtA Rhizobactin 1021 (siderophore) receptor/porin Gram-negative bacteria RhtA of Sinorhizobium meliloti
1.B.14.9.2Acr ferric achromobactin (hydroxycarboxylate siderophore) receptor/porin (Franza et al., 2005)Gram-negative bacteriaAcr of Erwinia chrysanthemi (AAL14566)

The ferric ferrichrome/aerobactin receptor/porin, IutA (Forman et al., 2007)

Bacteria IutA of Yersinia pestis (Q7CGN6)

Putative TonB-dependent heme receptor


TonB-dependent heme receptor of Campylobacter jejuni


TonB-dependent receptor of 700 aas, YncD, a probable iron transporter/receptor in the outer membrane.  Deletion of the orthologous yncD genes in Salmonella strains leads to attenuated strains, potentially useful for vaccine development (Xiong et al. 2012; Xiong et al. 2015). Its synthesis is depressed by inclusion of high glucose concentrations in the medium (Yang et al. 2011). YncD is a receptor for a T1-like Escherichia coli phage named vB_EcoS_IME347 (IME347) (Li et al. 2018).

YncD of E. coli


SchT (IutA) is capable of using dihydroxamate xenosiderophores, either ferric schizokinen (FeSK) or a siderophore of the filamentous cyanobacterium Anabaena variabilis ATCC 29413 (SAV), as the sole source of iron in a TonB-dependent manner (Obando S et al. 2018). Functions with the ABC uptake system having the TC# 3.A.1.14.24.

SchT of Synechocystis sp. PCC 6803