• Bacterium;
  • Outer membrane protein;
  • Porin;
  • Immunogene;
  • Adhesin;
  • Receptor


  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Channel activity, a prominent function for a major outer membrane protein
  5. 3Masked/other functions for a major outer membrane protein
  6. 4Conclusion
  7. Acknowledgments
  8. References

Porins form channels allowing the transport of molecules across lipid bilayer membranes. Their structure, location and large number on the bacterial surface lend them multiple functions. Porin loops are potential targets for adhesion to other cells and binding of bactericidal compounds to the surface of Gram-negative bacteria. Variation of the loop structure as a mechanism to escape immune pressure, or modulation of the porin expression in response to the presence of antibiotics, are survival strategies developed by some pathogenic bacteria. Porins may play a significant role as pathogenesis effectors.


  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Channel activity, a prominent function for a major outer membrane protein
  5. 3Masked/other functions for a major outer membrane protein
  6. 4Conclusion
  7. Acknowledgments
  8. References

The membranes of living cells form an efficient adaptative barrier that protects prokaryotic and eukaryotic genes and cellular machinery against external harmful agents, including heavy atoms and acidic or other damaging substances. At this impermeable boundary, the cells organise protein structures that form hydrophilic channels; these restricted entry checkpoints allow the selective uptake of required nutrients [1,2]. The study of these special transmembranal inserts soon led to the identification of the first purified bacterial pore-forming membrane proteins. Nakae characterised such a protein for the first time in 1976 and named it porin [3]. The first identified porins were OmpC and OmpF of the Gram-negative bacterium Escherichia coli[1], but several years later, the existence of porins was reported in Gram-positive and Gram-negative bacteria; at present both specific and non-specific pore-forming proteins have been found throughout both prokaryotes and eukaryotes.

Depending on their physicochemical properties and their conformational and environmental characteristics, bacterial porins can display either a trimeric or monomeric organisation [2]. OmpA of E. coli and OprF of Pseudomonas aeruginosa typify the monomeric group. OmpF of E. coli and porin of Rhodobacter capsulatus are examples of the trimeric family, and were the first porin structures solved [4,5]. The three monomer units making up the functional trimer are closely associated through numerous surface-exhibited loop (subunit) interactions [1,2,4,5], and only drastic conditions, e.g. harsh detergent such as sodium dodecyl sulfate at high temperatures (up to 70°C), will dissociate them. This tight conformation, inserted into the outer membrane, organises a compact molecule with specific, highly variable cell-surface-exposed domains involved in various activities (see below), which are especially resistant to degradative attacks.

A striking feature is the high level of expression of this major outer membrane protein class depending on the bacterial species and the environmental conditions, porins can reach about 104–106 copies per cell [2]. The synthesis of porins may be up- or down-regulated by the presence or absence of special molecules in the medium. Maltose and equivalent dextrins induce the expression of maltoporin LamB, and sucrose or fructose similarly regulates ScrY. Phosphate starvation allows the full expression of PhoE, the phosphoporin. The level of expression of osmoporin, e.g. E. coli OmpC, is governed by the ompB regulon, comprising envZ and ompR genes, the two-component regulatory system [1,6]. The expression of the osmoporin is up-regulated at high pH, high ionic strength and high temperature. Conversely, the expression of E. coli OmpF and of Klebsiella pneumoniae OmpK35, are down-regulated under the same conditions [1,6,7]. Additional regulation may also occur through the response elicited by antibiotics, heavy metals, detergents, bile salts, or aromatic compounds, which can decrease the amounts of porins in the outer membrane via several regulatory cascades involving mar or sox operons [6,8]. Moreover, several alterations occurring in the lipopolysaccharide (LPS) structure and outer membrane physiology can impair OmpF or OmpA expression, illustrating the crucial role of envelope components during the functional assembly of porins in the outer membrane [1].

2Channel activity, a prominent function for a major outer membrane protein

  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Channel activity, a prominent function for a major outer membrane protein
  5. 3Masked/other functions for a major outer membrane protein
  6. 4Conclusion
  7. Acknowledgments
  8. References

2.1Pore function

The channel, per se, is more than just a continuous regular channel ensuring the free passage of small hydrophilic molecules [1,2]. An important feature is an internal eyelet region formed by a long loop bent into the channel with its carboxy-negative cluster facing the positive charges from Arg/Lys residues derived from β-sheets belonging to the β-barrel wall. This special organisation creates an electrostatic field in the lumen that regulates the diffusion of the molecule through the constriction area. The functional parameters of the channel have now been well-documented using several techniques including reconstitution in artificial membranes, planar lipid bilayers, patch clamp and ‘liposome swelling’ approaches [9]. Electrophysiological studies provided extensive information concerning the size, conductance, selectivity and voltage gating of the channel characteristics, and yield a functional model of the pore protein inserted in the outer membrane. The role played by internal domains of pore structure during diffusion has been thoroughly investigated using different techniques. Channel size has been evaluated using polyamines as pore-blockers, molecular dynamics, computer simulations focusing on the loop flexibility, and atomic force microscopy investigations, probing the pH-induced channel closure of E. coli OmpF. These data support a new molecular understanding of pore function that is interactive and flexible. To determine the contribution of specific regions in these processes, various pore mutants have been isolated from the environment, chemically generated by random mutagenesis, or recently constructed from site-directed mutagenesis. The different studies carried out on these modified porins, mainly focusing on OmpC, OmpF, PhoE and LamB, highlighted the role of residues belonging to the lumen, or close to amino acids interacting with ones located in the channel. Several mutations have clearly demonstrated the strategic role of charged residues located inside the eyelet of OmpF porin: when some residues located inside the lumen, e.g. amino acids 16, 42, 82 and 119, were substituted, nutrient uptake or antibiotic susceptibility were severely altered (for example see [10–13]).

In addition, recent electrophysiological analyses have demonstrated that the excretion of endogenous cadaverin through porin can mimic a pore-blocker, similarly to external added polyamine [14]. This indicates that modulation of the pore closure can take place in growing bacterial cells in response to external stimuli such as acidic stress or charged compounds. This mechanism may play a prominent role during in vivo resistance towards chemical shocks, hydrophilic antibiotics such as β-lactams or fluoroquinolones.

2.2Regulation of porin expression

Bacteria must constantly monitor their environment through phenotypic modifications that require an adaptive response. In the case of nutrient limitation and changes in the osmolarity of the medium, Gram-negative bacteria adapt their outer membrane permeability by modulating the expression of porins. The biosynthesis of some enterobacterial porins, such as OmpF and OmpC (E. coli and Salmonella), are regulated by the ompB locus [6,15]. The ompB locus encodes OmpR–EnvZ, a two-component regulatory system, including EnvZ, a histidine kinase sensor, and OmpR, a transcriptional activator. At low osmolarity, OmpF predominates; alternatively at high osmolarity, ompF is repressed, and OmpC represents the major porin in the outer membrane. Some porins are also regulated by low nutrient levels, like OmpF and LamB, which are important for sugar uptake. For example, in E. coli the expression of OmpF protein, which forms large pores, is considerably increased (up to 20-fold) between 10−6 and 10−7 M glucose. At lower concentration of sugar and a lower growth rate, the bacteria switch off both LamB and OmpF biosynthesis, and the expression of the small OmpC channels is increased. The level of OmpF was more responsive to nutrient limitation than to medium osmolarity [1,6].


This unusual class of membrane proteins, which harbour no typical hydrophobic domains in their sequence involved in the membrane assembly, contains numerous β-barrel structures. The solved outer membrane protein structures, R. capsulatus porins, E. coli OmpF, PhoE and LamB generate an overview allowing a general consensus model protein containing 16-stranded β-barrels for non-specific porins, and 18 for sugar porins [2]. The local distribution of residues, hydrophilic and hydrophobic, is conserved among the trimeric non-specific porins derived from different Gram-negative bacteria. The presence of a ring of aromatic amino acids located near the merging area of the monomers anchors the protein within the lipid bilayer [2,4,5]. The refinement of their X-ray crystallographic structure clearly indicates the presence of several anti-parallel β-sheets, which organise the β-cylinder. It is important to mention the high preservation of domains corresponding to β-sheets within the porin superfamily, probably reflecting the strategy of well-adapted conformation used for an efficient stable functional assembly of pore proteins in the outer membrane.

X-ray diffraction studies show that the pore is built inside the cylinder by the membrane-spanning anti-parallel β-strands connected by short periplasmic turns and surface-exposed loops. The variability in the functional barrel construction is due to (i) differences in the lengths and orientations of the surface-exposed loops, (ii) differences in the lengths and arrangements of β-sheets, (iii) differences in the external LPS interactions inducing steric hindrance, and (iv) evolving subunit interactions. For further information on structure–function relationships, reviews described and discussed in detail the structural behaviour and evolution of the bacterial porins [2,9].

3Masked/other functions for a major outer membrane protein

  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Channel activity, a prominent function for a major outer membrane protein
  5. 3Masked/other functions for a major outer membrane protein
  6. 4Conclusion
  7. Acknowledgments
  8. References

The structure of porins (see the schematic representation of porin topology in Fig. 1), as well as the high level of their expression (104–106 molecules per cell), allow them to ensure other tasks than to link up out- and indoors of bacterial cells, through solute diffusion. Porins may affect several biological functions allowing a rapid adaptation and the survival of bacterial cells.


Figure 1. Transversal representation of a monomeric subunit from the OmpC/OmpF porin family. The figure illustrates the membrane topology of a monomeric subunit (for clarity) with protruding loops exposing various antigenic, receptor sites and the connecting loop. The location of functional domains, mouth, eyelet and periplasmic delta, of the channel is indicated inside the barrel. Evaluations of the respective sizes (indicated on the right side) are indicated from literature [2,4].

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3.1Role of porins in antibiotic resistance

In parallel to genetic approaches on channel functions of bacterial porins, extensive in vivo physiological investigations reported wide flexibility in porin expression, with regard to amounts and activities, in Gram-negative bacteria involved in severe infections in hospitals. For Neisseria meningitidis, K. pneumoniae and Enterobacter aerogenes, some documented clinical isolates exhibit a noticeable porin variability located mainly in the channel domains [7,16,17]. These variants exhibit an antibiotic resistance phenotype, which explains the persistence of bacterial colonisation despite the usual antibiotic therapy. The variable position maps in the eyelet area, and the main effect observed in these resistant clinical strains is associated with substitutions that introduce charged residues in place of neutral ones or amino acids with short side chains. This additional charge is projected inside the lumen and consequently perturbs the normal diffusion of antibiotics.

In addition to the modulation of pore size, variable levels of porin expression may play a significant role in antibiotic resistance, favouring onset of disease. Nosocomial outbreaks are mainly due to extended-spectrum β-lactamase (ESBL)-producing enterobacteria. Production of β-lactamase by these microorganisms inactivates most of the β-lactam antibiotics, and their resistance to other antibiotic groups, such as aminoglycosides and quinolones, prevent their eradication owing to the very restricted choice of drug.

In the presence of some antibiotics, bacterial pathogens switch off or decrease the expression of the porins concerned. Causality between loss of porins OmpC and OmpF and antibiotic resistance has been suggested in several reports, especially for E. coli and Salmonella typhimurium. Loss of porins in ESBL-producing K. pneumoniae strains has been shown to cause resistance to cefoxitin, increased resistance to third-generation cephalosporins and monobactams, and decreased susceptibility to fluoroquinolones. It was recently reported that most isolates of K. pneumoniae lacking expression of ESBLs expressed the two porins OmpK36 and OmpK35, whereas most isolates producing these β-lactamases expressed only OmpK36 porin, and OmpK35 porin was either very low or not expressed [18]. In other members of the Enterobacteriaceae family, resistance to carbapenems has been related to diminished outer membrane permeability and hydrolysis by overproduced chromosomal β-lactamase. More recently, the alteration of the functional structure of the pore has been demonstrated for β-lactam-resistant isolates [16,17].

3.2Receptor function

Given the special location and the high copy number of porins, it is hardly surprising that various functions have arisen and been selected during evolution, such as receptors of phages, bacteriocins, sites for antibody production by the immune system, binding sites for components of complement cascades, sites involved in the uptake of various nutrient transport complexes. These additional roles involve cell-surface-exposed loops belonging to one monomer subunit (Fig. 1), and in some cases the participation of a trimer surface (interacting loops) either as a receptor-binding site or as the conformational support of the site [26]. Porin loops are potential sites for the binding of bactericidal compounds to the surface of Gram-negative bacteria. The iron carrier in secretory fluids, lactoferrin, may use OmpC and PhoE porins of E. coli as high-affinity anchoring sites. The antibacterial activity of lactoferrin may rely, at least in part, on its ability to bind porins, thus modifying the stability and/or permeability of the bacterial outer membrane [19].

Porin proteins from different bacterial species, such as S. typhimurium, Salmonella minnesota, K. pneumoniae and Aeromonas hydrophila have been shown to activate complement via the classical or alternative pathway, after C1q binding [20,21]. Activation of this system by serum-sensitive bacteria leads to recognition and deposition of opsonic proteins (C3b or iC3b) on cell-surface-exposed sites. After this initial step, lysis of the sensitive microorganisms is initiated by the formation of the membrane attack complex (C5b to C9 [C5b–9]). Thus, various porin domains play a strategic role during this killing cascade.

Concerning the phage sites, the skilful use of various porin hybrids, such as OmpC–OmpF and OmpF–PhoE, has produced a map of receptor domains for Tu1a, Tu1b and TC45. A similar approach allowed the identification of the exposed loops involved in the colicin A and N binding sites. For instance, in the case of OmpF, several exposed and internal domains have been reported to be involved in the receptor step of colicin uptake and in the following translocation through the outer membrane. Deletions and substitutions of exposed amino acids evidenced the role of some residues in these receptor sites during colicin binding on E. coli surface [11].

3.3Porins as pathogenesis effectors

Among the numerous mechanisms involved in the interaction between soil bacteria and plant roots, the adhesion of these bacteria to the root surface is of major importance. For plant root-colonising bacteria only a few studies concerning the role of porins as root adhesins have been reported. It was shown that in vitro OmpC of Rahnella aquatilis was implicated in the adhesion of this bacterium to wheat roots [22], and OprF of Pseudomonas fluorescens in its adhesion to cereal roots [23]. Recently, in vivo expression technology was used to analyse genes expressed in Pseudomonas putida during colonisation of a plant-pathogenic fungus (Phytophthora parasitica). Three inducible genes were identified, among them genes encoding outer membrane porins, suggesting their role in fungus colonisation by P. putida[24].

Outer membrane porins, such as OmpD from S. typhimurium[25], OmpK36 from K. pneumoniae[20], and OmpC from Shigella flexneri[26] may act as virulence factors during the invasive processes of these bacteria. In the case of S. flexneri, OmpC has been shown to be involved in the invasion of epithelial cells [26]. The ompB and ompC knock-out mutants were considerably impaired in their virulence phenotypes. The ability of these two mutants to spread from cell to cell and to damage epithelial cells was seriously affected. The virulence of the ompB mutant of S. flexneri was restored by introducing a recombinant multicopy plasmid carrying the cloned ompC gene of E. coli, indicating that a functional OmpC protein was necessary and sufficient to restore the virulence [26]. In the case of Campylobacter jejuni, the main outer membrane pore protein was reported to exert a cytotoxic activity towards cultured cells [27], and so display cell membrane adhesion [28].

The role of porins in bacterial virulence has been reported for another Gram-negative bacterium, Vibrio cholerae, which causes the potentially fatal human disease cholera. The transcriptional activator ToxR that coordinates the expression of virulence factors, also modulates the expression of two outer membrane porins by inducing OmpU and repressing OmpT [29]. ToxR-dependent modulation of the outer membrane porins OmpU and OmpT seems to be critical for V. cholerae bile resistance, virulence factor expression, and intestinal colonisation, suggesting a relationship between porin and pathogenesis functions [30].

The most exciting example of porins as pathogenesis effectors concerns porB of Neisseria gonorrhoeae, the causative agent of a sexually transmitted disease. These gonococci colonise the mucosae of the urethra, endocervix, conjunctiva, fallopian tube, rectum, and pharynx. An important determinant trait contributing to the survival of these gonococci in host cells is porin (PorB). PorB, the major outer membrane protein of N. gonorrhoeae, functions as a classical porin, acting as an ion and nutrient transport channel in the outer membrane. Also, the porin of pathogenic Neisseria reportedly translocates from the outer membrane of the gonococci into artificial membranes as well as into host cell membranes [31,32]. The insertion process leads to the formation of a functional channel that is strikingly regulated by the eukaryotic host cell. Translocated neisserial porin induces apoptosis by causing a rapid calcium influx, followed by the activation of the calcium-dependent cysteine protease calpain, and the central apoptosis-executing molecules, the caspases [32]. These signalling events are organised to yield a co-ordinated response of cytoskeletal changes, phagocytosis, transcriptional activity and apoptosis. The pore channel formation is blocked in the presence of 10 mM ATP, preventing consequently the rapid Ca2+ signal elicited by porin and apoptosis [32]. These data suggest that through the ATP-sensor function of the porin, the pathogenic Neisseria will induce apoptosis only when the nucleotide level of host cells is low, as a consequence of low nutrient level.

3.4Immunological responses to porins

Some pathogenic bacteria are able to adhere or to interact with leukocytes trough porins. Negm and Pistol [33] showed that the OmpC porin of S. typhimurium mediates adherence to macrophages by using transposon mutagenesis to develop an OmpC-deficient mutant. Indications from this study support a contribution of the OmpC in initial recognition by macrophages, allowing the identification of regions of this protein that potentially participate in host cell recognition of bacteria by phagocytic cells [34]. Stimulation of leukocytes with either, porins or LPS from S. typhimurium may even slightly increase their transmigration through non-activated human endothelial cells in vitro [34], whereas transmigration increased remarkably during the simultaneous stimulation of endothelial cells by interleukin IL-1ss. In the case of Pasteurella multocida, porin and LPS are able to modulate inflammatory and immunological responses by affecting the release of several cytokines and the expression of their genes. They up-regulate the mRNA expression of IL-1α, IL-6, TNF-α, INF-γ and IL-12 p40 [35].

3.5Porin variation, an escape from immune suppression and phages

As reported above, surface-exposed molecules are essential for bacterial pathogenesis, but they are potential targets for the binding of bactericidal compounds and for recognition and suppression by the immune system. They may be recognised by antibody and complement, which may result in direct killing of the microorganism. To survive, microbial pathogens have developed various mechanisms to escape or overcome antibacterial defences, such as variation of surface-exposed constituents, a consequence of both mutation and DNA rearrangement [36]. Studies of antigenic variation of pathogens have important implications, especially for the development of porin-based vaccines. This is the case for neisserial porins, which are targets for serological typing schemes and candidates for inclusion in vaccines. The sequence variation in the porA gene of a clone of N. meningitidis (ET-15) during epidemic spread has been investigated [37]. Fourteen different porA alleles were identified among 38 ET-15 strains isolated from various geographic origins [37].

Porin polymorphism may also be a strategy for resistance to phages. Strains of E. coli O157:H7 collected from different sources were permissive to phage AR1, but resistant to phage T4, which normally infects K-12 strains of E. coli through contact with the outer membrane protein OmpC. A divergence between these strains in the OmpC amino acid sequence, consisting of 15 amino acid substitutions and two gaps (a five-residue deletion and a four-residue insertion) was reported [38]. Variation in the composition and pore function of major outer membrane pore protein P2 of Haemophilus influenzae, involved in cystic fibrosis has been reported [39]. DNA sequencing of ompP2 gene from clinical isolates revealed very few non-synonymous base differences, affecting the amino acid sequence of surface-exposed loops 4, 5, 6 and 8. These changes were suggested to affect the permeability of the porin channel and thus their susceptibility to β-lactam antibiotics [39].


  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Channel activity, a prominent function for a major outer membrane protein
  5. 3Masked/other functions for a major outer membrane protein
  6. 4Conclusion
  7. Acknowledgments
  8. References

Many results now confirm the involvement of bacterial porins in the pathogenicity and virulence of bacterial infection processes associated with innate pore-forming channels in the outer membrane or with the activity of various exposed binding sites. This novel aspect of porin behaviour may be related to its special localisation and structure: special localisation enabling its secretion in small vesicles in the environment, inducing fusion with eukaryotic membranes; special structure ensuring, via the LPS and subunit interactions, lower exposure of the antigenic domain, and exposed loops involved in ligand-receptor sites.

Moreover, bacterial and eukaryotic porins display structural and functional similarities. The latter feature allows bacterial porins to interfere with the ion composition of infected cells and thus disturb the activity of phagolysosome by constituting, jointly or independently of LPS, an accessory class of binding sites during the adhesive steps of bacterial colonisation/invasion. Given their special location and high expression level, it is not surprising to observe a large flexibility of exposed loops, which responds to ecological pressure, the immune system, phages or bacteriocins. Similarly, the variation in the cell-exposed domains can also reflect adaptation to the environment, surface charge, biofilms, root walls, detergents and epithelial cell surfaces. This adaptation may support the differential evolution of external loops from porins produced by Gram-negative bacteria belonging to separate ecological niches. In addition, the special conditions in a hospital environment (use of antibiotics and antiseptics), the break of natural barrier between various bacterial populations, play an important role in the process of selection/expression/modulation of porins, inducing large modifications of the permeability and the reactive surface of the bacterial membrane. The remarkable genetic flexibility of bacterial pathogens related to surface-exposed molecules needs to be considered in the context of vaccine development.


  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Channel activity, a prominent function for a major outer membrane protein
  5. 3Masked/other functions for a major outer membrane protein
  6. 4Conclusion
  7. Acknowledgments
  8. References

We apologise to those whose papers and important studies were not cited because of the publisher's space limitations. This work was supported by the Centre National de la Recherche Scientifique and the Commissariat à l'Energie Atomique, Institut National de la Santé et de la Recherche Médicale, The Institut Fédératif de Recherche 48, the Université de la Méditerranée, the Région PACA and Marseille-Métropole.


  1. Top of page
  2. Abstract
  3. 1Introduction
  4. 2Channel activity, a prominent function for a major outer membrane protein
  5. 3Masked/other functions for a major outer membrane protein
  6. 4Conclusion
  7. Acknowledgments
  8. References
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