Chemosensory systems are signaling pathways elegantly organized in hexagonal arrays that confer unique functional features to these systems such as signal amplification. Chemosensory arrays adopt different subcellular localizations from one bacterial species to another, yet keeping their supramolecular organization unmodified. In the gliding bacterium Myxococcus xanthus, a cytoplasmic chemosensory system, Frz, forms multiple clusters on the nucleoid through the direct binding of the FrzCD receptor to DNA. A small CheW-like protein, FrzB, might be responsible for the formation of multiple (instead of just one) Frz arrays. In this review, we summarize what is known on Frz array formation on the bacterial chromosome and discuss hypotheses on how FrzB might contribute to the nucleation of multiple clusters. Finally, we will propose some possible biological explanations for this type of localization pattern.

Introduction

Chemotaxis is the ability of cells to reorient in the environment and is essential to search for nutrients [1]; move towards favorable oxygen concentration, pH and temperature [2]; form multicellular structure [3]; infect host cells [4] and penetrate bacterial prey colonies [5].

In bacteria, chemotaxis is achieved by the aid of specialized signaling pathways known as Che (Chemotaxis) systems. Che systems in enteric bacteria include one or multiple receptors also termed Methyl-accepting Chemotaxis Proteins (MCP) that are activated upon binding to specific ligands [6,7]. Activated receptors, by means of the adaptor protein CheW, induce the autophosphorylation of a histidine kinase, CheA, which, in turn, transfers phosphoryl groups to the response regulator CheY (Table 1). Phosphorylated CheY (CheY-P) binds to FliM, inducing a change in the flagellar rotation from counterclockwise to clockwise. This switch of rotation results into a random reorientation of the bacterial cell body, a behavior also known as tumbling [8]. Upon binding of the MCPs to attractant ligands, cells tumble rarely and swim smoothly to continue moving in the same direction; conversely, in the presence of repellents, cells tumble frequently to increase the chances to reorient towards favorable environments and move away from the repellent molecules. CheZ rapidly dephosphorylates CheY-P, terminating the signal and preventing cells from tumbling for prolonged periods of time [9,10]. CheA-P can also transfer phosphoryl groups to CheB, which, together with CheR, constitutes the adaptation module. Methylation (CheR) and demethylation (CheB) reactions on specific glutamate residues on the MCP, increase and decrease, respectively, the sensitivity of the receptors for a given concentration of ligand, allowing cells to respond to a large range in concentration changes (Figure 1A and Table 1) [11–13].

Che proteins are organized in signaling arrays.

Figure 1.
Che proteins are organized in signaling arrays.

Schematic representation of the E. coli Che system (A) and M. xanthus Frz pathway (C). (B) MCP form trimers of dimers (each dimer is shown as a green circle), which, in turn, form hexagons connected with rings composed of the CheP5 domain (dark blue bars) and CheW (white bars). The light blue circles represent the CheP4 domain and, the red circles the interface between CheP5 and CheW. Rings containing six CheW proteins (shown at the center of the array) might serve to modulate the stability and activation of the system. A signaling unit is represented in the red box (Adapted from [60]).

Figure 1.
Che proteins are organized in signaling arrays.

Schematic representation of the E. coli Che system (A) and M. xanthus Frz pathway (C). (B) MCP form trimers of dimers (each dimer is shown as a green circle), which, in turn, form hexagons connected with rings composed of the CheP5 domain (dark blue bars) and CheW (white bars). The light blue circles represent the CheP4 domain and, the red circles the interface between CheP5 and CheW. Rings containing six CheW proteins (shown at the center of the array) might serve to modulate the stability and activation of the system. A signaling unit is represented in the red box (Adapted from [60]).

Table 1
Che and Frz protein functions.
Protein name E. coliHomolog in M. xanthusFunction
Tar, Tsr, Trg, Tap, Tag and Aer FrzCD Chemoreceptor or MCP (Methyl-accepting Chemotaxis Protein) 
CheA FrzE Histidine Kinase 
CheW FrzA and FrzB Adaptor protein 
CheR FrzF Methyltransferase 
CheB FrzG Methylesterase 
CheY FrzX and FrzZ Single domain response regulator 
CheZ none Dephosphatase 
Protein name E. coliHomolog in M. xanthusFunction
Tar, Tsr, Trg, Tap, Tag and Aer FrzCD Chemoreceptor or MCP (Methyl-accepting Chemotaxis Protein) 
CheA FrzE Histidine Kinase 
CheW FrzA and FrzB Adaptor protein 
CheR FrzF Methyltransferase 
CheB FrzG Methylesterase 
CheY FrzX and FrzZ Single domain response regulator 
CheZ none Dephosphatase 

A minimal functional unit is composed of two MCP trimers of dimers, a CheA dimer and two CheW (Figure 1B). In Escherichia coli, functional units are networked in complex hexagonal arrays that are anchored to the inner membrane thanks to MCP transmembrane domains [14–17]. By electron cryotomography, arrays appear as MCP hexagons interconnected with rings formed by the P5 domain of CheA and CheW. Each MCP hexagon is constituted by six MCP trimers of dimers with one MCP in the dimer connected with either CheAP5 or a CheW (Figure 1B) [15]. Che arrays have been observed in many bacterial and archeal species [18,19] and are responsible for the unique signaling properties of chemotaxis systems, such as signal amplification and sensitivity [20–23]. In some bacteria like Rhodobacter sphaeroides and Vibrio sp., certain MCP lack the transmembrane domains and form, together with CheA and CheW, arrays in the cytoplasm.

Besides their targeting to the membrane or positioning in the cytoplasm, chemosensory systems can adopt various subcellular localizations in different bacterial species. Arrays can be visualized, by fluorescence microscopy, as discrete clusters at the cell poles (E. coli, Bacillus subtilis and Vibrio sp.), in the cytoplasm (R. sphaeroides) or at the nucleoid (Myxococcus xanthus) [24–30]. A specific cellular localization can be perpetuated throughout the cell progeny by the aid of passive or active segregation mechanisms. For example, R. sphaeroides and Vibrio sp. employ homologs of the ParA protein to actively partition their chemosensory arrays among daughter cells, upon cell division [28,31]. On the other hand, E. coli and B. subtilis passively segregate their chemosensory systems along with the cell poles. In the next paragraphs, we will review some recent findings on the positioning of M. xanthus chemosensory clusters at the nucleoid. We will then discuss how this unique localization pattern might allow the correct segregation of these macromolecular complexes on cell division.

Myxococcus xanthus motility and chemotaxis

The Gram negative bacterium M. xanthus is an interesting model system to study motility and its regulation because it possesses two motility systems allowing movements on different surfaces and eight chemosensory systems [29,32,33]. The ability of M. xanthus to move mediates several cell group behaviors such as swarms on rich solid media, ripples during predatory behaviors and three-dimensional fruiting bodies upon nutrient deprivation [34]. Twitching or Social (S) motility mediates the formation of swarms and is mostly observed when cells are in groups [33]. That is because S motility requires the activity of polar Type IV Pili that extend and retract following the binding to exopolysaccharides (EPS) enveloping the neighboring cell surface or deposited on the substrate [35]. Cells can twitch as individuals on substrates mimicking EPS [36]. Gliding or Adventurous (A) motility features individual cell movement on hard surfaces and is powered by Agl/Glt focal adhesion complexes [32]. These complexes that cross the cell envelope from the cytoplasm to the cell exterior are assembled at the leading cell pole. Then, their transport from the cell front to the back, combined with the ability to bind the substrate, powers the cell translocation analogously to eukaryotic focal adhesion complexes [32].

M. xanthus can modulate its movement direction by biased reversals. A reversal is defined as a 180 degrees change in movement direction due to a switch of cell polarity where the leading pole becomes the lagging pole and vice versa [37]. By analogy with biased tumbling in enteric bacteria, it is thought that the modulation of the cell reversal frequency in response to the external environment can lead to directed movement. The same analogy led to classify substances that decrease the reversal frequencies as attractants (EPS and some lipids) [38] and those that induce reversals as repellents (short-chain alcohol) [36]. Unlike enteric bacteria where chemotaxis modulates single-cell swimming, the M. xanthus reversal frequency regulation is not limited to single-cell behaviors. Indeed, the rippling phenomenon observed during predation and consisting of groups of hundreds of cells moving in a co-ordinated manner, implies that the periodic reversals of these cells are also co-ordinated [5].

The Frz pathway

The Frz pathway is one of eight genetically distinct M. xanthus chemosensory systems [29]. It was discovered in 1979 by Morrison and Zusman during a search of M. xanthus mutants unable to form fruiting bodies [39]. The mutants were termed frz because instead of forming round-shaped fruiting bodies, they formed ‘frizzy' filaments in developmental conditions. The observation of single cells revealed the inability of frz mutants to reverse their movement direction even in the presence of repellent-like substances [40] suggesting that frizzy filaments result from unregulated cell movements rather than from defects in the developmental program. Frz genes were later shown to encode homologs of chemotaxis proteins organized in a signaling pathway [41].

Similarly to Che systems, the activation of the FrzCD receptor, a cytoplasmic methyl-accepting chemotaxis protein [42], triggers the autophosphorylation of the histidine kinase FrzE, a CheA–CheY fusion, on the conserved residue H49 [43]. Then, the phosphoryl group can be transferred to at least three CheY domains: one constituting the FrzX protein, also the main CheY of the pathway [37] and two contained in tandem in FrzZ, an accessory response regulator [44]. A fourth CheY domain contained in FrzE (FrzECheY) might also be phosphorylated. FrzZ and FrzECheY have important regulatory functions increasing the signaling capacity and precision of the system [36,43]. The Frz pathway also carries two CheW, FrzA and FrzB. While FrzA is a canonical CheW, FrzB has been shown to be an accessory protein important for the formation of multiple nucleoid Frz arrays (see below) [41,45]. FrzCD can be methylated and demethylated by FrzF and FrzG, respectively (Figure 1C) [46,47]. The Frz output FrzX induces the switch of polarity (reversal) of the A and S-motility machineries via a small GTPase (MglA), its cognate GTPase activating protein (MglB) and its guanine nucleotide exchange factors (RomX and RomR) [48–50].

Frz nucleoid clusters for signal amplification

It has been recently shown that the cytoplasmic FrzCD receptor forms foci localized at the center of the cell body, which is known to be the same cell region occupied by the nucleoid (Figure 2A) [42,51]. Like in other bacteria, the histidine kinase FrzE is essential for cluster formation, as in its absence Frz clusters are dispersed on the nucleoid (Figure 2B) [42]. The docking factor of Frz nucleoid clusters is contained in the N-terminal region of FrzCD and replaces the transmembrane domains that in E. coli MCPs dock the receptor to the inner membrane. The N-terminal DNA-binding domain of FrzCD consists of a small 20 amino-acid positively charged peptide that allows the binding of FrzCD to DNA in vitro and in vivo [42]. Interestingly, this region resembles the positively charged N-terminal tail that allows eukaryotic histones to assemble the nucleosome [52]. The recent findings on the unique FrzCD localization pattern raise at least two questions: do Frz clusters adopt a similar organization to Che arrays? What is the rationale behind the Frz localization at the nucleoid?

The Frz pathway forms arrays at the nucleoid.

Figure 2.
The Frz pathway forms arrays at the nucleoid.

(A) M. xanthus FrzCD-GFP localization at the nucleoid. The nucleoid is visualized with the DNA-DAPI staining (Adapted from [60]). (B) M. xanthus FrzCD-GFP localization in the indicated genetic backgrounds (Adapted from [42,45,60]).

Figure 2.
The Frz pathway forms arrays at the nucleoid.

(A) M. xanthus FrzCD-GFP localization at the nucleoid. The nucleoid is visualized with the DNA-DAPI staining (Adapted from [60]). (B) M. xanthus FrzCD-GFP localization in the indicated genetic backgrounds (Adapted from [42,45,60]).

Despite the lack of a direct visualization of FrzCD hexagons, a biological evidence that Frz proteins have allosteric interactions comes from their ability to produce an amplified response in the presence of a given signal [42]. Indeed, one of the main outcomes of the E. coli MCP array formation is the fact that, upon ligand binding, an activated receptor can transmit its active state to neighboring receptors through conformational changes. This phenomenon results in a cellular response (tumbling frequency) amplified as compared with the initial ligand concentration [23,53,54]. Similarly, it has been shown that upon the addition of increasing concentrations of a repellent-like molecule, M. xanthus single-cell reversal frequencies increase in a sigmoidal manner. On the other hand, in the absence of the FrzCD DNA-binding and thus in the absence of Frz clusters, single-cell reversals increase linearly with the amount of the repellent [42].

Electron cryotomography showed that cytoplasmic MCPs, instead of forming a layer running parallel to the inner membrane, form two mirroring layers sandwiched by two CheA–CheW layers, similar to at least two cytoplasmic receptors, TlpT from R. sphaeroides and DosM from V. cholerae [55,56]. This organization might be due to the lack of a scaffold (such as the membrane in E. coli) for the nucleation of an MCP monolayer. The fact that FrzCD binds the nucleoid suggests that Frz arrays, rather than forming sandwich-like structures like the cytoplasmic homologs, might form a monolayer running parallel to the nucleoid surface like transmembrane MCPs. Indeed, in the sandwich configuration the MCP N-terminal domains are orientated towards the inside of the bilayer, leaving likely no room for DNA. Finally, it is possible that FrzCD molecules adopt an intermediate configuration with some zones of the array organized in monolayers and some as a sandwich. This third possible organization might especially apply to the single FrzCD cluster formed in the absence of FrzB, due to the high local concentration of FrzCD molecules (see below). In fact, sandwich-like structure have been also observed in conditions where chemoreceptor molecules were expressed at high levels [55].

Why do Frz clusters bind to the nucleoid? FrzCD might localize in the cytoplasm to sense yet unknown metabolic ligands. However, the absence of a clear ligand-binding domain in FrzCD suggests that this receptor could also be activated by interacting with other proteins [57]. It is also possible that FrzCD is activated by some DNA functions (replication or transcription) to couple the regulation of motility with the cell cycle. The binding of FrzCD to DNA is independent of the DNA sequence, CG content and length. These ‘aspecific' FrzCD–DNA interactions suggest that the only function of the Frz-nucleoid binding might be to ensure a scaffold for Frz cluster formation. In this case, the nucleoid would replace the membrane ensuring array formation and, as a consequence, signal amplification and cooperativity.

How do Frz proteins form multiple clusters? FrzB, a stabilizing factor

The formation of multiple chemosensory complexes in E. coli has been associated with the ability of Che arrays to auto-assemble stochastically at random positions in the membrane. The stochastic self-assembly model implies that, in the absence of a specific anchoring factor, receptors can spontaneously nucleate new clusters if they are far enough (at least 1 µm) from existing clusters, or being absorbed by an old cluster in proximity [58]. In other species, the positioning of Che proteins is driven by a specific protein factor. For example in Vibrio, Che array formation at the cell pole requires the interaction of CheW with the ParP protein. ParP is in turn recruited by the ParA-homolog, ParC [59]. The ParP/ParC-mediated localization of Vibrio Che proteins is an active mechanism, as it requires ATP hydrolysis by ParC. Therefore, it differs from the stochastic self-assembly of E. coli Che arrays that is not energy consuming.

Because the FrzCD binding to the nucleoid is not DNA-sequence specific, Frz proteins can nucleate anywhere on the nucleoid. It has also been shown that the number of Frz clusters per cell increases linearly with the nucleoid size [42]. Therefore, the mechanisms of Frz cluster assembly might be more similar to the stochastic self-assembly of membrane Che arrays, than to some active localization mechanisms [60]. Beside the scaffold used for cluster formation (membrane or nucleoid), Frz and Che clusters, respectively, differ by the fact that E. coli Che arrays do not form uniformly in the membrane, but preferentially at the cell poles. On the other hand, Frz clusters appear more homogeneous in size and intensity all along the nucleoid [25,42]. The preference of the E. coli clusters for the poles suggests the existence of factors that stabilize clusters at this site [61].

It has been recently shown that Frz clusters on the nucleoid might be stabilized by the CheW-like protein FrzB [45]. In fact, in the absence of FrzB, Frz clusters collapse into a single bright cluster localizing at random positions on the nucleoid (Figure 2B) [45]. Unlike FrzA, the canonical CheW of the Frz pathway, FrzB cannot interact with FrzE nor mediate its autophosphorylation in vitro. In fact, FrzB lacks two β-strands (β4 and β5) that have been described to be essential in the CheW:CheAP5 interaction. This region is present in FrzA and, strikingly, the FrzA β4 and β5 in FrzB converts the latter into a canonical CheW [45]. These results, together with genetic evidence, suggest that the loss of the CheAP5–CheW interacting region from FrzB might have been selected to control the formation and distribution of multiple nucleoid Frz chemosensory arrays. Such organization is essential for Frz to function correctly as deletions in frzB lead to severe reversal frequency phenotypes.

How can FrzB stabilize Frz clusters? As mentioned above, Che arrays are constituted by hexagons of MCP trimers of dimers networked by CheAP5–CheW rings (Figure 1B) [15]. If FrzB cannot interact with FrzE, instead of participating in the formation of rings with FrzEP5, it could either form 6-FrzB rings or break the networking of FrzCD trimers of dimers with FrzEP5–FrzA rings (Figure 3). Either way could represent a way to favor the formation of small Frz clusters. As for the formation of 6-FrzB rings, it has been recently shown that, in addition to CheAP5–CheW rings, the formation of Che networks implies the formation of six-member CheW rings that only interact with the MCPs (Figure 1B) [17,23,62]. The 6-CheW rings have been visualized by cryoEM, and their proposed function is to stabilize Che arrays by favoring allosteric interactions. Six-FrzB rings might stabilize small Frz clusters, which would otherwise become a single cluster. Alternatively, FrzB might favor the formation of small Frz clusters by interrupting the networking of MCP trimers of dimers with CheAP5–CheW rings (Figure 3). Finally, an extra stabilizing factor might be required for the correct activation and stabilization of chemosensory arrays at the nucleoid. Such stabilizing factor would be dispensable when receptors arrays are tightly anchored to the inner membrane.

Proposed model on how FrzB might confer plasticity to Frz clusters.

Figure 3.
Proposed model on how FrzB might confer plasticity to Frz clusters.

(A) FrzB allows the formation of small Frz clusters by breaking the networking of MCP trimers of dimers with CheP5–CheW rings. (B) FrzB participates to the formation of 6-CheW rings to stabilize small Frz clusters, which would otherwise fuse into one single cluster. (C) Single large cluster formed in the absence of FrzB (Adapted from [45]).

Figure 3.
Proposed model on how FrzB might confer plasticity to Frz clusters.

(A) FrzB allows the formation of small Frz clusters by breaking the networking of MCP trimers of dimers with CheP5–CheW rings. (B) FrzB participates to the formation of 6-CheW rings to stabilize small Frz clusters, which would otherwise fuse into one single cluster. (C) Single large cluster formed in the absence of FrzB (Adapted from [45]).

Why do Frz proteins form multiple clusters? A passive segregation mechanism

The first obvious outcome of multiple cluster formation is sensitivity. Indeed, while multiple ‘small' clusters formed by the wild type are active and sensitive even in the presence of low signal, the unique large cluster formed in the absence of FrzB is only active in the presence of high signal [45]. This is likely due to the increased cooperativity of large clusters [63]. Another possibility could be to prevent that the diffusion of FrzX-P becomes a limiting factor in the control of the polar and lateral motility motors due to the length of M. xanthus cells (5–10 µm in average) [37].

Besides being important for the correct Frz functioning, the formation of multiple nucleoid-associated clusters might also allow the segregation of Frz proteins without the aid of an active segregation mechanism. In the case of R. sphaeroides, cytoplasmic TlpT receptors form a single cluster in the middle of cells. To ensure that the progeny is able to perform chemotaxis soon after division, a ParA-like protein, PpfA is required to first duplicate the TlpT cluster and then actively and equally partition the two clusters between the two daughter cells [31].

In M. xanthus, the presence of multiple distributed clusters would represent a simple mechanism to segregate clusters during cell division along with the DNA and without the need of a faithful partitioning system, as required for the single cluster of R. sphaeroides. The lack of a faithful segregation system in M. xanthus is further suggested by the fact that in a ΔfrzB cell population, while the majority of cells have a single cluster, a fifth of the population have no cluster. It is possible that, in the absence of FrzB and during cell division, only one daughter cell inherits the single Frz array and the other one will synthesize a new one [45].

Perspectives

  • Importance of the field. While the polar localization has long represented the paradigm for the positioning of bacterial chemosensory systems, studies on different bacterial species have revealed the existence of many examples diverging from the paradigm. Even if the physiological importance of forming Che arrays has been robustly established, the biological reasons behind a specific localization pattern or a defined number of clusters remains mostly elusive. The localization of M. xanthus Frz clusters at the nucleoid represents so far a unique example. However, the Frz localization pattern might be relevant to other macromolecular complexes different from the Frz system, but sharing similar anchoring strategies at the nucleoid. FrzCD binding to the nucleoid only requires a small positively charged sequence at the N terminus rather than a specific sequence. Thus, the Frz localization might be widespread. Finally, the discovery of new accessory Che proteins, such as FrzB, important in the establishment of the Frz localization pattern, might allow the identification of new functions and additional regulation mechanisms controlling the cellular responses operated by chemosensory systems.

  • Summary of the current thinking. The formation of multiple Frz clusters at the nucleoid occurs in two steps: first, FrzCD recruits FrzA and FrzE at the nucleoid to form a cluster. Then, FrzB mediates the nucleation of multiple Frz arrays by two possible proposed mechanisms: either by stabilizing small arrays or by inhibiting the expansion of clusters (Figure 3). New clusters might form as cells grow and the nucleoid increases in size by a stochastic self-assembly mechanisms [58].

  • Comment on future directions. It will be interesting, for the future, to experimentally determine by which mechanisms FrzB mediate the formation of multiple Frz clusters on the nucleoid. In this direction, it remains essential to visualize by electron-cryotomography the supramolecular organization of Frz proteins within arrays. Are Frz arrays organized as a monolayer running parallel to the nucleoid surface or rather organized as a bilayer like other described cytoplasmic arrays? Are 6-CheW rings visible within Frz arrays? A better understanding of the determinants of Frz array formation at the nucleoid might also provide hints on the Frz signal, which remains mostly unknown. Finally, it would be interesting to explore to which extent this type of cellular organization is common to other bacterial macromolecular complexes. In this sense, the Frz example provides new perspectives to the role of the bacterial nucleoid as a scaffold for the spatial control of cellular functions.

Abbreviations

     
  • EPS

    exopolysaccharides

  •  
  • MCP

    Methyl-accepting Chemotaxis Proteins

Acknowledgements

I would like to thank Dorothée Murat and Julien Herrou for their feedback and critical readings of this manuscript. I would also like to thank Tam Mignot and Annick Guiseppi for their constant support. Our research on chemotaxis is supported by the CNRS and Aix-Marseille University.

Competing Interests

The author declares that there are no competing interests associated with this manuscript.

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