TY - JOUR
AU - Bange, Gert
AB - Bacteria differ in number and location of their flagella that appear in regular patterns at the cell surface (flagellation pattern). Despite the plethora of bacterial species, only a handful of these patterns exist. The correct flagellation pattern is a prerequisite for motility, but also relates to biofilm formation and the pathogenicity of disease-causing flagellated bacteria. However, the mechanisms that maintain location and number of flagella are far from being understood. Here, we review our knowledge on mechanisms that enable bacteria to maintain their appropriate flagellation pattern. While some peritrichous flagellation patterns might occur by rather simple stochastic processes, other bacterial species appear to rely on landmark systems to define the designated flagellar position. Such landmarks are the Tip system of Caulobacter crescentus or the signal recognition particle (SRP)-GTPase FlhF and the MinD/ParA-type ATPase FlhG (synonyms: FleN, YlxH and MinD2). The latter two proteins constitute a regulatory circuit essential for diverse flagellation patterns in many Gram-positive and negative species. The interactome of FlhF/G (e.g. C-ring proteins FliM, FliN, FliY or the transcriptional regulator FleQ/FlrA) seems evolutionary adapted to meet the specific needs for a respective pattern. This variability highlights the importance of the correct flagellation pattern for motile species. flagellum, biological pattern, GTPase, ATPase, cellular polarity INTRODUCTION Self-organization and maintenance of cellular polarity, asymmetry and the patterned arrangement of substructures are essential features of life, and should have been subject to strict evolutionary control. In contrast to the highly structured and compartmented eukaryotic cell, the bacterial cell exhibits only a low degree of ‘obvious’ order and usually lacks cellular compartments. Therefore, bacteria have traditionally been viewed as disordered ‘bags of enzymes’ that mainly aim to grow and divide. Only in recent years it has become clear that bacteria organize their cellular contents in a highly spatio-temporal manner. This is best seen by the appearance of a diverse spectrum of cell shapes, life cycles or precisely positioned cellular appendages that exist between the different bacterial species. The flagellum represents one of the largest bacterial surface structures and enables bacteria to swim through liquids or swarm over semisolid surfaces. The cellular appearance of flagella is species-specific and varies in terms of place and number (flagellation pattern). While architecture, protein composition and function of flagella are conserved and well described; only little is known on how bacteria reproducibly establish place and number of their flagella during each round of cell division. Because the phenotypic appearance of flagellation patterns can be easily addressed by microscopy and as such served as one of the earliest taxonomic criteria in microbiology, it offers an excellent ‘phenotype’ for investigating the molecular mechanisms and inventory that control bacterial self-organization. Moreover, the surveillance of different flagellation patterns relies in part on the same set of evolutionarily related proteins. Therefore, flagellation patterns might provide an excellent example for studying the molecular evolution of mechanisms underlying the diversity of bacterial species. Here, we aim at reviewing our knowledge on the molecular mechanisms that enable bacteria to maintain the correct flagellation pattern during each round of division. THE BACTERIAL FLAGELLUM The bacterial flagellum is a highly elaborated rotary motor whose main structural and functional features have been subject to intense research over the past decades and are not the main focus of this review (e.g. reviewed in: Doetsch and Sjoblad 1980; Chevance and Hughes 2008; Erhardt, Namba and Hughes 2010; Altegoer et al.2014). In short, the complete flagellar machinery consists of approximately 25 different proteins in variable stoichiometry, and the flagellar structure can be divided into the basal body with a cytoplasmic cup-like structure (C-ring or switch complex), a membrane-embedded part, and the rod, hook and filament structures extending towards the extracellular space (Fig. 1). Flagella of Gram-negative and positive bacteria mainly differ in the architecture of the rod and rod-associated structures. The basal body contains the motor structures (reviewed in: Minamino, Imada and Namba 2008) and the flagellar type III secretion system (fT3SS) that is required for flagellar assembly (Fig. 1) (Macnab 2004). Figure 1. Open in new tabDownload slide Scheme of the bacterial flagellum from a Gram-positive (left) and a Gram-negative (right) bacterium. The major building blocks are color-coded: basal body (red and yellow), Rod (pale green), Hook (light green) and the Filament (green). The flagellum can either rotate clockwise (CW) or counterclockwise (CCW). Figure 1. Open in new tabDownload slide Scheme of the bacterial flagellum from a Gram-positive (left) and a Gram-negative (right) bacterium. The major building blocks are color-coded: basal body (red and yellow), Rod (pale green), Hook (light green) and the Filament (green). The flagellum can either rotate clockwise (CW) or counterclockwise (CCW). Flagella of most species can rotate in counterclockwise- and clockwise mode powered by proton and, in some cases, by sodium gradients to drive bacterial movement (reviewed in: Berg 2003). Motor-generated rotation is translated into motion through the hook and filament structures. The hook constitutes a universal joint (Samatey et al.2004) that transmit motor rotation from the rod onto the flagellar filament, a long, tubular filament composed of ten thousands of flagellin subunits, forming an Archimedes-like screw to propel the bacterium through liquids (Berg 1975; Samatey et al.2001). The rotational state of the flagellar motor is commonly regulated and switched, respectively, through the cytoplasmic C-ring that receives inputs from one or more associated chemosensory systems through the response regulator CheY in a phosphorylation-dependent manner (reviewed in: Sourjik and Armitage 2010; Sourjik and Wingreen 2012). Motor structures and C-rings from different flagellated species show significant structural differences (reviewed in: Zhao, Norris and Liu 2014; Minamino and Imada 2015) and protein compositions (Schuhmacher et al.2015). The functional reasoning underlying this diversity likely has manifold reasons in environmental adaption and is far from being understood. DIVERSITY OF BACTERIAL FLAGELLATION PATTERNS Although the flagellar structure is overall conserved, flagella appear at distinct location and in defined numbers that are characteristic for each bacterial species. The pattern is adjusted to efficiently move the cell within the species’ corresponding environment (e.g. polar flagella for fast swimming in liquid environments, peritrichous flagellation for moving through more viscous environments or across surfaces) (reviewed in: Kearns 2010; Altegoer et al.2014). Despite the plethora of bacterial species, only a handful of these flagellation patterns have been observed in microbiology (Fig. 2). Localization of a flagellum is either restricted to the cell pole(s) or appears along the lateral side, whilst flagellar number differs from a minimum of 1 via a maximum of 25 for Bacillus subtilis to as many as several hundred in swarming cells of Vibrio parahaemolyticus (Shinoda and Okamoto 1977). Major flagellation patterns are (i) monotrichious (e.g. Bdellovibrio, Caulobacter, Pseudomonas, Vibrio, Shewanella), (ii) amphitrichous (e.g. Campylobacter), (iii) lophotrichous (e.g. Helicobacter, some Pseudomonas species, Agrobacterium) and (iv) peritrichous (e.g. Escherichia coli, B. subtilis, (Sino) Rhizobium sp.) (Fig. 2). The purple non-sulfur photosynthetic bacterium Rhodobacter sphaeroides displays a flagellum approximately at midcell and represents a member of the medial-flagellated bacteria that navigates by turning the rotation of the flagellum ‘ON’ (run) and ‘OFF’ (tumble) instead of switching rotation direction (Armitage and Macnab 1987; Pilizota et al.2009). Figure 2. Open in new tabDownload slide Bacterial species vary in number and location of their flagella. Negative-stained electron micrographs from polar-flagellated P. aeruginosa, C. crescentus, the lophotrichous H. pylori, the amphitrichous C. jejuni and the peritrichously flagellated B. subtilis and E. coli. The insets schematically indicate the respective patterns. Figure 2. Open in new tabDownload slide Bacterial species vary in number and location of their flagella. Negative-stained electron micrographs from polar-flagellated P. aeruginosa, C. crescentus, the lophotrichous H. pylori, the amphitrichous C. jejuni and the peritrichously flagellated B. subtilis and E. coli. The insets schematically indicate the respective patterns. Some bacterial species even exhibit two independent flagellar systems encoded in separate gene clusters at different genomic locations. Many Vibrio species, Aeromonas, Rhodospirillum, and other species continuously produce a polar flagellum (encoded by one flagellar operon) that enables their swimming in liquids. Swarming over surfaces or in viscous environment or surface attachment is supported by a multitude of lateral flagella (encoded by a secondary flagellar operon) (reviewed in: McCarter 2004; Merino, Shaw and Tomas 2006). In addition, subpopulations of Shewanella species possess a single lateral flagellum besides their primary polar one that increase directional persistence of swimming to support efficient navigation (Bubendorfer et al.2014). Each of the described flagellation patterns is maintained during bacterial cell division and formation of a fully functional flagellar system often requires more time than a full cell cycle. Thus, tight spatio-temporal control and definite mechanisms might be required for the surveillance of flagellar place and number. In the following, we will review our present knowledge on mechanisms underlying spatio-temporal flagellar positioning. HOW DO BACTERIA DEFINE FLAGELLAR PLACE AND NUMBER? Peritrichous flagellation of Salmonella typhimurium and E. coli The Gram-negative bacteria E. coli and S. enterica are long-standing models for studying flagellar motility, the flagellum and flagellar assembly. They exhibit a prevalent peritrichous flagellation pattern with five to six flagellar filaments distributed over the cell body (Leifson 1960) (Fig. 2). Several studies demonstrated that the number of flagella may vary depending on the environmental conditions and cell cycle, and increases in number upon surface contact to facilitate swarming across surfaces (e.g. (Harshey and Matsuyama 1994; Aizawa and Kubori 1998; Chilcott and Hughes 2000; Turner, Ryu and Berg 2000; Ping 2010). In Salmonella, flagellar number does not increase upon surface contact and/or in the swarming motility state (Partridge and Harshey 2013). Despite the long history of studying flagella in both organisms, little is known on how flagella place and number are established in these organisms. So far, evidence for the positioning of multiprotein complexes within the cell envelope mainly comes from studies on the localization of the chemotaxis signaling arrays (reviewed in: Jones and Armitage 2015). Multiple mechanisms have been suggested, including stochastic self-assembly by ‘diffusion and capture’ mechanisms and cellular landmarks. The clustering of chemoreceptors by stochastic self-assembly is proposed to result in the observed non-uniform distribution of clusters, somewhat resembling that of the flagellation pattern in the same species (Maddock and Shapiro 1993; Sourjik and Berg 2000; Thiem, Kentner and Sourjik 2007; Thiem and Sourjik 2008). Thus, the peritrichous E. coli flagellation pattern may simply arise through a similar stochastic nucleation pattern and would not require any landmark proteins, and a sufficient amount of flagellar filaments along the cell axis would ensure that both mother and daughter cell would be equipped with flagellar filaments to immediately allow effective swimming and chemotaxis after cell division and separation (Mears et al.2014). This model may be supported by the observation that partially assembled motors, visualized as fluorescent fusions to components of the flagellar basal body, display high motility within the cell envelope (Fukuoka et al.2007; Li and Sourjik 2011). Once formed, the flagellum is unlikely to move to another position again (Ping 2010). However, in E. coli, flagella are, in sharp contrast to chemotaxis clusters, rarely observed at the cell poles. In addition, the flagellar number tends to be higher at the cell half marked by the ‘old’ cell pole after cell division. It has been suggested that this observed asymmetry of flagellation increases chemotaxis efficiency (Ping 2010). Therefore, the E. coli flagellation pattern is, on average, not random but depends on localization of the ancestor's flagellar systems. In addition, it might also be subject to direct spatio-regulatory control, e.g. to discourage flagellar formation at the cell pole. We therefore expect that additional, yet unknown, mechanisms are active in E. coli and related species to establish the appropriate peritrichous flagellation patterns. This has been shown for the similar flagellation pattern of B. subtilis as will be elaborated below. In contrast to a random localization of flagellar systems as it might occur in E. coli or Salmonella, the specific localization of flagella in other species has been demonstrated to be defined and mediated by corresponding ‘landmark’ proteins, which recruit the flagella to their designated position. LANDMARK SYSTEMS FOR LOCALIZATION OF FLAGELLA: TIP AND FLHF/G Regulation of the polar flagellum in Caulobacter (and other α-proteobacteria) Due to its complex life cycle, the α-proteobacterium Caulobacter crescentus represents a long-standing model system to study microbial cell cycle regulation and polarity (reviewed in: Kirkpatrick and Viollier 2012; Tsokos and Laub 2012). This species has a replicative-quiescent swarmer state in which the cells are motile by a single polar flagellum (Fig. 2). A cylindrical extension of the cell body, the so-called stalk, is formed at the same pole and serves as an adhesion organelle. In the pre-divisional cell, a new flagellum is built at the opposite cell pole. After completion of division and cytokinesis, the motile (non-replicative) flagellated daughter cell is released, while the stalked mother cell may immediately enter another replicative cycle. A number of studies have identified several factors involved in mediating flagellar localization and formation. In Caulobacter, TipN, a polytopic membrane coiled-coil protein, serves as the ‘landmark protein’ for directing the flagellum to the old cell pole. Notably, during late cytokinesis, TipN relocalizes from the old to the nascent cell pole, thus marking this new pole as the reference point for flagellar assembly in the following cell cycle (Huitema et al.2006; Lam, Schofield and Jacobs-Wagner 2006). In the absence of TipN, the cells produce one or several flagella that are mislocalized. TipN is not exclusively mediating flagellar placement as cells lacking or overproducing this protein exhibit several severe polarity defects. Polarly localized TipN recruits a second transmembrane protein, TipF, which can bind the second messenger molecule c-di-GMP. The intracellular level of c-di-GMP is varying depending on the cell cycle progression and increases in the dividing cell entering the S-phase. Binding of c-di-GMP stabilizes TipF and enables polar recruitment by TipN (Davis et al.2013). TipF, in turn, recruits a third flagellar positioning factor, the bitopic protein PflI to the cell pole (Obuchowski and Jacobs-Wagner 2008; Davis and Waldor 2013). TipF is also required to direct building blocks of the flagellar basal body, FliF, FliG and FliM, to the cell pole (Davis et al.2013). In contrast to mutants lacking TipN or PflI, a deletion of tipF results in non-flagellated cells, strongly indicating that TipF is not only required for localization but also for functional assembly of the flagellar machinery (Huitema et al.2006). Thus, although several questions remain, these studies demonstrate how spatio-temporal control of flagellar assembly in Caulobacter is intimately linked to cell cycle progression. However, the α-proteobacteria are highly heterogeneous with respect to their flagellation patterns (Obuchowski and Jacobs-Wagner 2008). Homologous proteins to Caulobacter TipN and TipF can be identified in several, but not all genera within this highly diverse group of proteobacteria. It is yet unknown whether putative orthologs to TipN and/or TipF have similar roles in other α-proteobacteria, and how flagellar placement is achieved in those species apparently lacking this set of proteins. Another major yet unsolved question is how TipN localizes to the appropriate positions within the cell during the cell cycle. Noteworthy, targeting of TipN to the future flagellated pole depends on early and late cell division proteins and physically interacts with the Tol-Pal system (Schofield, Lim and Jacobs-Wagner 2010; Yeh et al.2010; Davis et al.2013). Regulation of diverse flagellation patterns by FlhF and FlhG The proteins FlhF and FlhG [earlier also: YlxH (van Amsterdam and van der Ende 2004), FleN (Dasgupta, Arora and Ramphal 2000), MotR (Campos-Garcia et al.2000) and MinD2 (Leipe et al.2002)] are essential for establishing correct place and quantity of flagella in several bacterial species (as detailed below). Both proteins are conserved among many bacterial species and clades. When both flhF and flhG are present, they always appear as a transcriptional unit with flhG adjacent downstream to flhF (Bange et al.2011). Noteworthy, flhFG are preceded by genes encoding the innermembrane core of the fT3SS with flhA adjacent upstream of flhF (Bange et al.2007). Also, FlhA and FlhF have been recognized as functional equivalents to flagellar master regulators in Helicobacter pylori (Niehus et al.2004). The genetic context observed downstream of flhFG exhibits a high degree of variability. Although FlhF and FlhG proteins are conserved among the species at the sequence level, they are essential to the physiological appearance of a wide range of different flagellation patterns that is summarized in the following: Monotrichious Most of the behavior, cell biology and molecular genetics on FlhF/G have been performed in the following polar-flagellated, monotrichious bacteria: V. cholera, V. alginolyticus, Pseudomonas aeruginosa, P. putida and Xanthomonas oryzae (summarized in: Kazmierczak and Hendrixson 2013; Altegoer et al.2014) (Table 1). Deletion of flhF resulted in absence and/or the mislocalization of flagella leading to swimming/swarming defects. In contrast, overproduction of FlhF in Vibrio and Pseudomonas species resulted in hyper-flagellated strains severely impaired in motility (Pandza et al.2000; Correa, Peng and Klose 2005; Kusumoto et al.2006; Green et al.2009). In contrast to flhF, the deletion of flhG leads to hyper-flagellated strains of Vibrio, Shewanella putrefaciens and P. aeruginosa (Campos-Garcia et al.2000; Kusumoto et al.2006, 2008; Murray and Kazmierczak 2006; Schuhmacher et al.2015). Table 1. Factors regulating number and location of flagella. (A) The table summarizes proteins involved in maintaining the correct flagellation pattern, and their occurrence in the given model organisms. Variations in the domain architectures of the C-ring proteins FliM (green–blue), FliN (blue) and FliY (orange–blue) are schematically shown. The N-terminal domain of FliY from Campylobacter and Helicobacter shows certain homology to the CheC-domain, although no function has been shown so far. It has therefore been displayed transparent and with dashed contour. The conserved N-terminal ‘EIDAL’ motif is colored in yellow. (B) Illustrates the structure of different domains of the C-ring proteins FliM and FliN/Y in more detail [EIDAL motif taken from pdb: 1F4V (Lee et al.2001), FliM-middle-domain pdb: 2HP7 (Park et al.2006), FliN-domain pdb: 1O6A, FliY-middle-domain pdb: 4HYN (Sircar et al.2013)]. Open in new tab Table 1. Factors regulating number and location of flagella. (A) The table summarizes proteins involved in maintaining the correct flagellation pattern, and their occurrence in the given model organisms. Variations in the domain architectures of the C-ring proteins FliM (green–blue), FliN (blue) and FliY (orange–blue) are schematically shown. The N-terminal domain of FliY from Campylobacter and Helicobacter shows certain homology to the CheC-domain, although no function has been shown so far. It has therefore been displayed transparent and with dashed contour. The conserved N-terminal ‘EIDAL’ motif is colored in yellow. (B) Illustrates the structure of different domains of the C-ring proteins FliM and FliN/Y in more detail [EIDAL motif taken from pdb: 1F4V (Lee et al.2001), FliM-middle-domain pdb: 2HP7 (Park et al.2006), FliN-domain pdb: 1O6A, FliY-middle-domain pdb: 4HYN (Sircar et al.2013)]. Open in new tab Taken together, it seems that FlhF and FlhG execute opposing physiological roles. Although the underlying molecular mechanism is far from being understood, FlhG might act as negative regulator that controls flagellar number, while FlhF might mark the flagellar assembly point and, in many species, directly or indirectly serves as a positive regulator for flagellar synthesis (discussed in: Kazmierczak and Hendrixson 2013). Amphitrichous In amphitrichous bacteria, FlhF and FlhG have so far only been studied in Campylobacter jejuni. Similarly to monotrichious-flagellated bacteria, deletion of flhF and flhG resulted in the absence of flagella and hyper-flagellated cells, respectively (Balaban, Joslin and Hendrixson 2009; Balaban and Hendrixson 2011). Most interestingly, however, cells showed severe defects in cell division as indicated by ‘minicell’ phenotypes (Balaban and Hendrixson 2011). Lophotrichous The lophotrichous-flagellated bacterium H. pylori exhibits two to six flagella that are arranged around one cell pole. Loss of FlhG (YlxH in H. pylori) results in non-flagellate cells that are unable to swim (van Amsterdam and van der Ende 2004). Peritrichous The physiological role of FlhF has been investigated in B. subtilis and B. cereus that exhibit approximately 25 and 12 peritrichous flagella per cell, respectively, that are absent from the cell poles (Salvetti et al.2007; Guttenplan, Shaw and Kearns 2013). In both species, deletion of flhF leads to mislocalization of flagella, while in B. cereus also flagellar number is reduced to 1–3. Deletion of flhG in B. subtilis results in mislocalization of flagella that appear in tufts from constrained loci on the cell (Guttenplan, Shaw and Kearns 2013). In addition, high-resolution microscopy shows that flagellar basal bodies are aggregated. Interestingly, no flhG is present in B. cereus and the flagellar basal body rod protein FlgG is encoded adjacent downstream of flhF instead of flhG (Salvetti et al.2007). The signal recognition particle (SRP)-like GTPase FlhF FlhF is a GTPase that belongs to the small subfamily of signal recognition particle (SRP)-type GTPases with only two more members: the signal sequence binding protein Ffh and the SRP-receptor FtsY. Both are essential regulators for the cotranslational insertion of membrane proteins (reviewed in: Grudnik, Bange and Sinning 2009; Akopian et al.2013; Bange and Sinning 2013). FlhF, Ffh and FtsY share the conserved NG domain that includes the GTPase (G-domain) and a regulatory domain (N-domain) (Fig. 3A). While Ffh and FtsY form a GTP-dependent heterodimer through their NG domains, GTP-bound FlhF forms a homodimer (Shen et al.2001; Egea et al.2004; Focia et al.2004; Bange et al.2007). Although the role of the Ffh/FtsY heterodimer and its GTPase activity during SRP-mediated protein targeting is well known (Grudnik, Bange and Sinning 2009; Akopian et al.2013), only little is understood on the functional role of the FlhF GTPase homodimer for flagellation pattern control (Fig. 3B). Figure 3. Open in new tabDownload slide FlhF and FlhG regulate various flagellation patterns. (A) Domain architecture of the SRP-GTPase FlhF (green) and MinD-like ATPase FlhG (orange). The GTPase elements G1–G5 and insertion box (I-box) of FlhF are indicated. For FlhG, the activator helix, P-loop (also Walker A), Switch regions I and II and membrane targeting sequence (MTS) are shown. (B) Molecular switch mechanism of FlhF (left) and FlhG (right). The SRP-GTPase FlhF forms GTP-dependent homodimers (green, pdb: 2PX3; Bange et al.2007), which represents the ‘ON’ state of canonical GTPases. Upon interaction of FlhF with the N-terminus of FlhG (orange helix) an activator complex is formed (green, orange pdb: 3SYN; Bange et al.2011) that leads to subsequent stimulation of the FlhF GTPase. Upon GTP-hydrolysis the FlhF homodimer might dissociate and FlhF enters into its monomeric ‘OFF’ state. FlhG forms ATP-dependent homodimer (‘ON’ state, orange, pdb: 4RZ1; Schuhmacher et al.2015), which associate to the cytoplasmic membrane through the C-terminal MTS (red). After ATP hydrolysis, the homodimer falls apart. Monomeric FlhG (‘OFF’ state, orange, pdb: 4RZ2; Schuhmacher et al.2015) localizes in the cytosol due to protection of the MTS. In their ‘ON’ and ‘OFF’ states, FlhF and FlhG might be able to interact with specific effector proteins that than specifically control of number and location of flagella. Figure 3. Open in new tabDownload slide FlhF and FlhG regulate various flagellation patterns. (A) Domain architecture of the SRP-GTPase FlhF (green) and MinD-like ATPase FlhG (orange). The GTPase elements G1–G5 and insertion box (I-box) of FlhF are indicated. For FlhG, the activator helix, P-loop (also Walker A), Switch regions I and II and membrane targeting sequence (MTS) are shown. (B) Molecular switch mechanism of FlhF (left) and FlhG (right). The SRP-GTPase FlhF forms GTP-dependent homodimers (green, pdb: 2PX3; Bange et al.2007), which represents the ‘ON’ state of canonical GTPases. Upon interaction of FlhF with the N-terminus of FlhG (orange helix) an activator complex is formed (green, orange pdb: 3SYN; Bange et al.2011) that leads to subsequent stimulation of the FlhF GTPase. Upon GTP-hydrolysis the FlhF homodimer might dissociate and FlhF enters into its monomeric ‘OFF’ state. FlhG forms ATP-dependent homodimer (‘ON’ state, orange, pdb: 4RZ1; Schuhmacher et al.2015), which associate to the cytoplasmic membrane through the C-terminal MTS (red). After ATP hydrolysis, the homodimer falls apart. Monomeric FlhG (‘OFF’ state, orange, pdb: 4RZ2; Schuhmacher et al.2015) localizes in the cytosol due to protection of the MTS. In their ‘ON’ and ‘OFF’ states, FlhF and FlhG might be able to interact with specific effector proteins that than specifically control of number and location of flagella. Besides the NG domain, all FlhF proteins contain an N-terminal domain of basic character (B-domain) that seems to be natively unfolded (Fig. 3A) (Bange et al.2007). In V. cholera, the B-domain has been shown to be involved in recruiting the flagellar MS-ring constituent FliF to the cell pole (Green et al.2009). Interestingly, the B-domain shows significant variations in size and conservation among the species, suggesting that the B-domain might exert species-specific functions. Further studies are required to address the role of the B-domain in greater detail. It is also unknown, how FlhF is localized to the appropriate cell pole, which has been shown to occur independently of any other flagellar components in the polarly flagellated Vibrio (Kusumoto et al.2008; Green et al.2009). The MinD-like ATPase FlhG The crystal structure of FlhG revealed that it is a close structural homolog of the MinD ATPase, which is central to cytokinetic Z-ring formation during cell division (Schuhmacher et al.2015). FlhG and MinD share the conserved ATPase fold including the catalytic elements required for ATP and magnesium binding as well as hydrolysis (Fig. 3A) (Ono et al.2015; Schuhmacher et al.2015). As MinD (Wu et al.2011), FlhG forms homodimers that are dependent on ATP and phospholipids (Schuhmacher et al.2015) (Fig. 3B). Phospholipid interaction of FlhG is mediated through an autonomous and transplantable membrane-targeting sequence (MTS) at its C-terminus in a fashion similar to MinD or the signal recognition particle receptor FtsY (Szeto et al.2003; Parlitz et al.2007; Schuhmacher et al.2015). Structural and biochemical analysis showed that MTS-mediated membrane binding and ATP-dependent homodimerization of FlhG are intimately connected (Schuhmacher et al.2015). Therefore, FlhG cycles between two mutually exclusive states: an ATP-bound homodimer that interacts with membrane and an ADP-bound (or nucleotide-free) monomer, which is unable for functional membrane interaction and, thus, likely resides in the cytoplasm (Fig. 3B). In contrast to MinD, FlhG proteins harbor an N-terminal α-helical extension (activator helix; Bange et al.2011) in which a conserved ‘DQAxxLR’ motif is present. FlhF and FlhG are direct interaction partners (Parrish et al.2007; Kusumoto et al.2008; Bange et al.2011; Ono et al.2015). The activator helix mediates FlhF/G interaction and provides cocatalytic residues for GTP hydrolysis to FlhF (Bange et al.2011) (Fig. 3B, ‘Activator complex’). Furthermore, in Pseudomonas and some Xanthomonas species no ‘DQAxxLR’ motif can be identified in the N-terminal extension of FlhG (Kazmierczak and Hendrixson 2013; Schniederberend et al.2013). Therefore, slight molecular differences between the otherwise highly conserved FlhGs might be relevant for flagellation pattern formation. However, a more systematic and interspecies analysis is required to clarify this question. Intertwined cycles of FlhF and FlhG Both FlhF and FlhG are nucleotide-binding proteins that cycle between two mutually exclusive states: a monomeric and nucleotide-dependent homodimeric state (Bange et al.2007; Schuhmacher et al.2015) (Fig. 3B). Both cycles are connected through stimulation of transition of the GTP-bound FlhF homodimer into the GDP-bound (or nucleotide-free) FlhF by FlhG (Bange et al.2011) (Fig. 3B, ‘Activator complex’). Our current knowledge suggests that the regulatory FlhF/G circuit seems widely conserved. However, it is not known at which point FlhF and FlhG interact with each other and when FlhG stimulates the GTPase of FlhF. Moreover, it is unclear how both proteins can be involved in regulating different flagellation patterns? An answer to this question moonlights when having a closer look at the interaction partners of FlhF and FlhG in differently flagellated organisms that will be detailed in the following (Table 1): FlhF and FlhG interaction partners Flagellar C-ring proteins The flagellar C-ring is composed of three proteins (i.e. FliG, FliM and FliN/FliY) that assemble at the cytoplasmic face of the membrane embedded MS-ring (Chevance and Hughes 2008). While FliM (and FliG) are highly conserved among the bacterial species, C-rings differ in the domain architecture of the FliN and FliY proteins (Table 1). FliN and FliY as well as FliM share a conserved C-terminal FliN-homology domain. In the monotrichous-flagellated Vibrio, Shewanella, Pseudomonas and Caulobacter, the peritrichous-flagellated E. coli and Salmonella Thyphimurium as well as some Helicobacter and Campylobacter species FliN only consists of this C-terminal FliN-homology domain. Interestingly, in the genome of many Campylobacter and Helicobacter species both FliN and FliY are present at different loci. In these organisms, FliY is composed of the FliN-homology domain and an additional N-terminal domain that may resemble a CheC-like phosphatase. The actual function however, has not been assessed experimentally so far. In B. subtilis, FliY is composed of the conserved C-terminal FliN-homology domain, a CheC-like phosphatase domain in the middle and a conserved N-terminal motif (‘EIDAL’ motif) that is also present at the N-terminus of FliM (Table 1) (Szurmant et al.2003; Szurmant, Muff and Ordal 2004). FlhG acts during C-ring assembly and interacts with components of the flagellar C-ring in the polarly and peritrichously flagellated bacteria S. putrefaciens and B. subtilis (Schuhmacher et al.2015). However, while FlhG interacts with FliM in the polarely flagellated S. putrefaciens, FliY is the corresponding binding partner in the peritrichiously flagellated B. subtilis. Therefore, it can be speculated that topological differences within the C-ring proteins might also contribute to flagellation pattern formation. However, a precise picture of how diversity of C-ring components contributes to flagellation pattern formation is still lacking. Transcription factor FleQ (FlrA) In P. aeruginosa, the FlhG ortholog FleN has been shown to interact with the main flagellar regulator FleQ in a yeast two-hybrid screen (Dasgupta, Arora and Ramphal 2000) (Table 1). FleQ is a c-di-GMP-responsive transcription factor that consists of three domains: an N-terminal FleQ-domain, an AAA+ ATPase and a C-terminal helix-turn-helix domain for DNA binding (Hickman and Harwood 2008; Baraquet and Harwood 2013). Interaction of FlhG and FleQ is independent on ATP, and the FleQ/FleN complex binds to the promoters of pel, fleSR and flhA in P. aeruginosa (Dasgupta and Ramphal 2001; Jyot, Dasgupta and Ramphal 2002; Hickman and Harwood 2008). FlhG inhibits the ATPase activity of FleQ, which might result in down regulation of flagellar gene expression (Baraquet and Harwood 2013). The FleQ/FleN/c-di-GMP interaction directly links localization to control of transcription and might be required to restrict the number of flagella formed at the cell pole. Whether this is similarly true for other bacterial species remains to be elucidated. FleQ homologs are annotated as FlrA in Aeromonas, Vibrio and Shewanella and have been shown to be important for biogenesis of the polar flagellum in these species (Canals et al.2006; Syed et al.2009; Wilhelms et al.2011). However, while FlhG regulates flagellation patterns in numerous different species, the presence of FleQ or FlrA seems to be restricted to polar/lophotrichous-flagellated species of the γ-proteobacteria (Table 1). Genome analysis of the polar amphitrichously flagellated C. jejuni and the peritrichously flagellated B. subtilis, for example, shows no evidence for FleQ/FlrA proteins. HubP In V. cholera and V. parahaemolyticus, microscopic studies using GFP-labeled FlhG revealed that at least part of the protein occurs at the flagellated cell pole (Kusumoto et al.2008; Yamaichi et al.2012). For V. cholera, it has recently been demonstrated that a polytopic membrane protein, HubP, is required to recruit FlhG to this pole as in a strain lacking HubP, FlhG was either diffusely distributed or localized in a non-polar focus. HubP consists of an N-terminal periplasmic region harboring a predicted peptidoglycan-binding LysM domain, and a cytoplasmic region containing 10 imperfect repeats of an amino acid sequence highly enriched in acidic amino acids resulting in a rather low pI (3.22) of the protein. HubP can be directly targeted to the cell pole, and its periplasmic domain seems to be a major determinant for this process. In addition to the recruitment of FlhG, HubP also seems to be important for the correct localization of two other MinD/ParA-type ATPases, ParA and ParC. While a HubP mutant was severely affected in efficient chemotactic swimming, only a very minor fraction of the cells exhibited a flagellation phenotype slightly reminiscent of a DflhG strain. Although HubP is important for the polar localization of FlhG, FlhF was observed to polarly localize independently suggesting that polar targeting of FlhF occurs by mechanisms independent of HubP. Working Hypothesis for FlhF/G-mediated control of flagella place and number Summarizing the current knowledge, we here present a working hypothesis describing how FlhF/G might maintain place and number of flagella in different flagellation patterns. At present, we imagine the following major steps. FlhF targets the first building block to the future flagellar assembly site (Fig. 4, Step A). The mechanism by which FlhF achieves this ‘targeting’ step is completely unclear. The B-domain that significantly varies between different FlhF homologs seems to play an important role. Also, landmark proteins (e.g. HubP) and/or lipid compositions might support the targeting function of FlhF. Presence or absence of landmark proteins/lipids and differences within the B-domain might be important criteria of why FlhF homologs can be involved in different flagellation patterns (Table 1). However, future studies are required to address these questions in a systematic manner. After FlhF marked the future flagellar site, assembly of the basal body will proceed. In the cytoplasm, basal body assembly ends when the C-ring is completed upon association of FliM/FliN(Y) to FliG at the nascent C-ring structure (Fig. 4, Step B). Independent of nucleotides, monomeric FlhG binds FliM/FliN(Y) in the cytoplasm and assists their association into the nascent C-ring (via FliG). The role of the structural diversity of the flagellar C-ring proteins, and its consequences on the mechanism of FlhF/G need to be subject to future research. Moreover, it is not clear whether FlhG recruits FliM/FliN(Y) to FliG or vice versa. We prefer the idea that association of FliM/FliN(Y) into the C-ring recruits FlhG to (i) the nascent flagellar structure and (ii) the membrane. In the consequence, FlhG would be able to interact with FlhF and to stimulate its GTPase activity (activator complex, also Fig. 3B). Thus, FlhF would be inactivated (Fig. 4, Step C). FlhG being in close proximity to the membrane may also allow the interaction of its MTS with lipids that in turn facilitates ATP-dependent homodimerization of FlhG. At present, the functional role of the FlhG homodimer is rather enigmatic. Also, we don't know how the ATP-dependent homodimer is released from the membrane and whether release factors stimulate the ATPase activity of FlhG (Fig. 4, Step D). However, release of FlhG from the membrane might allow its interaction with transcription factors (e.g. FleQ) that in turn disables transcription of flagellar genes required to initiate further rounds of flagellar assembly. Figure 4. Open in new tabDownload slide Working model for flagella place and number regulation by FlhF/G. At present, we imagine four major steps (from A to D). FlhF and FlhG are shown in green and orange, respectively. The B-domain is indicated as green, dotted line. ‘T’ and indicates ATP/GTP bound to FlhF/G, respectively. The membrane targeting sequence (MTS) of FlhG is shown in yellow. Putative landmark proteins, special lipids and transcription factors are in blue, red and cyan, respectively. For reasons of simplicity, components of the C-ring are not detailed (red). DNA and membrane are in gray. Membranes and components of the basal body are shown in gray, as well. Figure 4. Open in new tabDownload slide Working model for flagella place and number regulation by FlhF/G. At present, we imagine four major steps (from A to D). FlhF and FlhG are shown in green and orange, respectively. The B-domain is indicated as green, dotted line. ‘T’ and indicates ATP/GTP bound to FlhF/G, respectively. The membrane targeting sequence (MTS) of FlhG is shown in yellow. Putative landmark proteins, special lipids and transcription factors are in blue, red and cyan, respectively. For reasons of simplicity, components of the C-ring are not detailed (red). DNA and membrane are in gray. Membranes and components of the basal body are shown in gray, as well. This mechanism would elegantly explain how FlhG regulates the correct flagellar number. Noteworthy, FlhG has been shown to interact with the transcription factor FleQ. However, FleQ/FlrA homologous are limited to polar-flagellated bacteria (Table 1). We therefore speculate that other FlhF/G-dependent flagellation patterns rely on yet unknown transcription factors regulated by FlhF/G. CONCLUDING REMARKS Taken together, we are just beginning to understand the mechanisms by which bacteria establish place and number of their flagella and stably maintain these patterns during each round of cell division. While some studies have suggested stochastic mechanisms to be responsible to establish flagellation patterns, studies on two systems, TipN/F and FlhF/G, suggest rather distinct molecular mechanisms for the spatio-temporal regulation of flagellar placement. However, much information is missing to draw the exact regulatory networks and mechanisms. Taken together, flagellation patters offers excellent systems for investigating the molecular inventory and evolution of bacterial self-organization. We thank Dan Kearns (Indiana) and Victor Sourjik (Marburg) for discussion and comments on the manuscript. We thank Dave Hendrixson (Texas), Barbara Waidner (Marburg), Knut Drescher (Marburg), Martin Thanbichler and Kathrin Bolte (Marburg) as well as Albert Siryaporn and Yi Shen (Princeton) for kindly providing original electron micrographs of flagellated bacteria to this review. The LOEWE program of the state of Hesse, Germany supported this work (to GB). JSS is a fellow of the Fonds der Chemischen Industrie (FCI). Conflict of interest. None declared. REFERENCES Aizawa SI Kubori T Bacterial flagellation and cell division Genes Cells 1998 3 625 34 Google Scholar Crossref Search ADS PubMed WorldCat Akopian D Shen K Zhang Xet al. 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TI - How bacteria maintain location and number of flagella?
JF - FEMS Microbiology Reviews
DO - 10.1093/femsre/fuv034
DA - 2015-11-01
UR - https://www.deepdyve.com/lp/oxford-university-press/how-bacteria-maintain-location-and-number-of-flagella-klYtRh20dj
SP - 812
EP - 822
VL - 39
IS - 6
DP - DeepDyve
ER -