Abstract
Life’s processes absolutely require inorganic phosphate for structural and energetic purposes. Escherichia coli has developed sophisticated mechanisms to acquire phosphate and to maintain intracellular amounts at optimal levels. The processes by which these simple cells maintain stable intracellular concentrations of phosphate are termed phosphate homeostasis, which involves mechanisms to balance the import, assimilation, sequestration, and export of phosphate. This chapter introduces the proteins involved in phosphate homeostasis and reviews information concerning the multiple phosphate transporters and the mechanisms by which they are regulated. It also introduces new concepts of how this bacterium responds to elevated extracellular levels of phosphate and presents a model for the integration of all of these processes to achieve homeostasis. The predominant importers are PitA, PitB, and the PstSCAB complex. Assimilation, or the incorporation of Pi into organic molecules, occurs primarily through the formation of ATP. Gene regulation relies on the PhoB/PhoR two-component system and the formation of a signaling complex at the membrane. The amount of intracellular phosphate can be fine-tuned through the formation or degradation of polyphosphate. Polyphosphate formation requires adequate supplies of ATP. In addition, when intracellular phosphate levels become too high, phosphate can be exported through PitA, PitB, or the YjbB transporters.
Keywords
- phosphate homeostasis
- ABC transporter
- phosphate transporter
- polyphosphate
- two-component signal transduction
1. Introduction
Inorganic phosphate (Pi) is essential for life. For example, it is found in the hydrophilic ends of the amphipathic lipids in the cellular membranes that define the boundaries of a cell. Together with the sugars ribose or deoxyribose, it makes up the structural backbone of DNA or RNA through its phosphodiester bonds. The cell’s energy currency is based upon the energy released from the hydrolysis of the phosphoanhydride bonds between the phosphates of ATP or of the other nucleotides. Moreover, the biochemical activities of many proteins are regulated by the phosphorylation of specific amino acids—histidine and aspartate in bacteria, as well as serine, threonine, and tyrosine.
Because of its essential roles, cells must maintain intracellular Pi pools at optimal levels. In bacteria, such as
The primary Pi importers in
The presence of the PhoBR signal transduction system underscores the need for maintaining a minimal intracellular level of Pi when extracellular Pi is limiting. That too much intracellular Pi can also be a problem is underscored by the phenotype of a
2. The multiple Pi importers
2.1. PitA and PitB—the low-affinity Pi importers
The low-affinity PitA and PitB transporters utilize the energy stored in the proton-motive force to bring neutral metal-Pi complexes into the cell [6, 25, 26]. These homologous proteins each contain 499 amino acid residues and show 80.8 and 89.8% sequence identity and similarity, respectively (see Figure 1A). Amino acid identities between the two proteins are indicated by vertical lines and similarities are indicated with two dots. A membrane topology model for these two proteins was created using the SCAMPI2 web server [27] and is shown in Figure 1B. This model predicts that PitA and PitB have 10 transmembrane helices with the N- and C-termini facing the periplasm. The sequences of the predicted transmembrane helices are surrounded by green boxes in Figure 1A. Support for this Nout-Cout topology model comes from a recent paper in which the authors tagged the C-termini of 601 inner membrane proteins from
Analysis of the kinetic properties of Pi uptake in whole cells where
It was originally thought that
PitA and PitB are members of the PiT family of Pi transporters within the transporter classification database (TC #2.A.20) [30] and the PHO4 family within the Pfam database [31]. These families include bacterial, archaeal, and eukaryotic members, suggesting that these Pi transporters developed early in evolution and that they continue to play important functions in all domains of life. A conserved signature sequence has been identified in both the N- and C-terminal ends of these transporters that has the common core sequence of
It has recently been suggested that neither PitA nor PitB play primary roles in Pi transport, but function instead for the purpose of metal ion transport [4]. However, considering the homologies between PitA and PitB with other Pi transporters from other organisms, it seems unlikely that they are retained in this genome primarily to function as transporters of divalent metal cations, which have their own primary transporters, as well [36]. Clearly, further work is needed to better understand the roles of PitA and PitB in Pi homeostasis.
2.2. PstSCAB—the high-affinity Pi importer
The PstSCAB protein is a high-affinity Pi transporter that has a
The Pst transporter is most highly expressed when environmental Pi levels are low. For this reason, it was assumed that it played its most important role in Pi transport under those conditions. More recently, it has been proposed that it plays the primary role in Pi transport under all conditions [4]. The expression of the
3. The two-component signal transduction system for Pi homeostasis
Two-component-signaling systems constitute the most common signaling pathways in bacteria [48]. These pathways regulate many important cellular processes ranging from cell development and virulence, to motility and metabolism, and most species have over 10–20 different two-component systems [49]. Most frequently, they are composed of receptors on the cell periphery and signal-processing components and targets in the interior of the cell. These pathways rely on a phospho-transfer reaction between the histidine residues of sensor kinases, which generally receive input from the cell surface, and a conserved aspartate residue within the response regulators, which are located in the cytoplasm [50]. Response regulators are most frequently, but not always, transcription factors that interact with RNA polymerase [51].
3.1. PhoB and PhoR—the transcription factor and the histidine kinase
In
PhoR is a homodimeric, bifunctional histidine autokinase/phospho-PhoB phosphatase. When environmental Pi is limiting, it autophosphorylates on a conserved histidine residue and subsequently donates this phosphoryl group to PhoB, but when Pi is plentiful, it removes the phosphoryl group from phospho-PhoB [57, 58]. PhoR is an integral membrane protein that is not predicted to contain a significant periplasmic domain but does contain a membrane-spanning region, a cytoplasmic charged region, a Per-ARNT-Sim (PAS) domain (Pfam: PF00989, PAS) [59], and prototypical dimerization/histidine phosphorylation (DHp; Pfam: PF06580, His_kinase) and catalytic ATP-binding (CA; Pfam: PF02518, HATPase_c) domains at its C-terminus (see Figure 3) [57]. PAS domains generally function in signal perception activities [60]. Since PhoR does not contain a significant periplasmic sensory domain, it is assumed that its PAS domain senses a cytoplasmic signal that reflects extracellular Pi concentrations, but the nature of the signal is not completely known. The CA domain harbors the enzymatic activity for transferring a phosphoryl group from ATP to the conserved histidine residue of the DHp domain. The DHp domain consists of a four-helix bundle with the conserved phospho-accepting histidine residue being positioned midway on one face of one of the helices. It has been shown that phosphorylation of PhoR occurs in cis, where the CA domain of one of the monomers phosphorylates the His residue of the same polypeptide chain [61]. The DHp domain also contains all of the residues necessary for phospho-PhoB phosphatase activity [57]. We propose that the control of the opposing kinase and phosphatase activities of PhoR involves the constraint of the CA domains to prevent their access to the DHp domain and simultaneously exposing the residues of the DHp domain that are required for phosphatase function (see Figure 3). If this proposal is correct, then how are the interactions between the different PhoR domains controlled?
3.2. PstSCAB—the sensor of extracellular Pi
In addition to its role in Pi transport, the Pst transporter is also required for signal transduction. Because PhoR does not have a periplasmic domain, it has been assumed that this transporter is the ultimate sensor of extracellular Pi [5]. In fact, if any of the Pst proteins are absent, the Pho regulon becomes unregulated, leading to the overexpression of Pho regulon genes [5]. Thus, the default biochemical activity of PhoR is an autokinase and the role of the Pst transporter is to negatively regulate this activity and to stimulate its phospho-PhoB phosphatase activity. There are two possibilities for how the Pst protein may function to control the activity of PhoR. The first is by controlling intracellular Pi levels. If PhoR senses intracellular Pi, most likely through its PAS domain, then the Pst system may function by controlling the amount of Pi within the cell. This model seems unlikely for two reasons. Intracellular Pi has been measured by phosphorous nuclear magnetic resonance (31P NMR) and has been shown to be constant under conditions in which the Pho regulon is both repressed and derepressed [2]. Also, there are several mutations in
3.3. PhoU—the adaptor protein
In addition to the PstSCAB protein, PhoU is also required for Pi-signal transduction, but not for transport through the complex [21]. When
Two general classes of models have been previously suggested for how PhoU participates in the signaling pathway. It may mediate the formation of a signaling complex between the PstSCAB transporter and PhoR [5, 64] or it may produce a soluble messenger that is recognized by the cytoplasmic domains of PhoR (consistent with observations reported by Hoffer and Tommassen [67] and by Rao and Torriani [68]). The following section presents new evidence in favor of the Pi-signaling complex model.
3.4. Protein interactions within the Pi-signaling complex
It has recently been demonstrated through bacterial two-hybrid analysis and through co-elution experiments that PhoU interacts with both the PhoR protein and PstB [66]. The two-hybrid experiments used the BACTH system [69]. Adenylate cyclase from
3.5. Conformational signaling model
To answer the question of how PhoR senses the signaling activity of the Pst transporter, we propose that PhoR interacts differently with the alternate outward- and inward-facing conformations of the transporter that are sampled throughout the transport cycle. When Pi is limiting, the transporters are not actively importing Pi and reside primarily in the outward-facing conformation. We propose that this conformation contacts PhoU in such a manner that it does not interact with both the PAS and CA domains of PhoR, which promotes its autokinase activity. It is only under Pi-replete environments when Pi import is occurring that the Pst transporter adopts the inward-facing conformation. We propose that in this conformation, it interacts with PhoU in such a manner to constrain the CA domain of PhoR so that its phosphatase activity is stimulated.
To test this model, we have recently created two
4. The response to high levels of extracellular Pi
Clues to understanding how
PolyP is found in all kingdoms of life [81, 82]. It is a linear chain of variable length of Pi residues that are linked by phosphoanhydride bonds. The cellular amounts of polyP are controlled through its polymerization and depolymerization, presumably to meet cellular needs for free Pi. PolyP can be synthesized from ATP by polyP kinase, encoded by the
To enhance biological removal of Pi from wastewater, Kato et al. cloned the
In addition to its role as a Pi and energy store, PolyP has many other important functions in
4.1. The Tn-seq experiment—identifying the players of the high-Pi response
In order to further investigate cellular processes involved in Pi homeostasis when cells are grown in conditions of high environmental Pi, we performed a Tn-seq experiment. Tn-seq relies on the ability to saturate a bacterial genome by transposon mutagenesis. Cells are grown in a selective environment and individual transposon insertions are mapped using next-generation-sequencing protocols. The frequency of insertions in each gene is used to analyze the importance of each gene under those growth conditions. Those genes that receive few or no insertions are identified as essential (no insertions under any conditions), conditionally essential (no or few insertions under one condition), or conditionally important for fitness (reduced insertion frequency under one particular condition) (see Figure 4).
Wild-type
To identify genes that are important for growth in high-Pigrowth conditions, we sorted from low to high each of the genes based upon the quotient of the number of hits in high-Pi media divided by the total number of hits in all three media. We were particularly interested in genes with few hits in the high-Pi medium and were able to identify many genes whose functions are important for fitness under these growth conditions. As mentioned above, the high-Pi growth medium that we employed was also high in osmolarity. As an internal control to identify genes that were important for this growth condition, we were able to identify many top hits as occurring in genes that are known to be important in a high osmolarity response, such as
We also identified genes that are known to be involved in the control of the Pho regulon, for example, each of the
4.2. Pi homeostasis model and questions for further research
While the general outlines of Pi homeostasis have begun to be filled in, there are still important questions that remain. How do cells sense intracellular levels of Pi to control polyP synthesis/degradation and Pi export? What are the roles of the genes that are repressed by the PhoBR system? What are the functions of the unknown genes that were identified by Tn-seq to be important for fitness in very high levels of environmental Pi? What are the control mechanisms for the expression of PitA and PitB? Why does
5. Conclusion
Pi homeostasis is essential for life’s basic processes. Without the ability to control intracellular levels of Pi within optimal levels, cells would be unable to maintain energy stores, synthesize nucleic acids and phospholipids, or carry out central metabolic pathways. The molecular mechanisms by which
Acknowledgments
I thank Ramesh Vuppada, a Master’s student in our laboratory, who provided the preliminary results about the signaling states of the alternate conformations of PstB and Tanner Robinson, an undergraduate student, for the preliminary Tn-seq results. I also thank the many undergraduate and graduate students who have contributed to the ongoing work and discussions in the laboratory. Work from our laboratory was supported by Public Health Service grant R15GM96222 from the National Institute of General Medical Sciences.
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