Current Topic pubs.acs.org/biochemistry
Three-Dimensional Distribution of Phospholipids in Gram Negative Bacteria Samuel Furse*,† and David J. Scott‡,§ †
MBI, Department of Molecular Biology, University of Bergen, Thormøhlensgate 55, 5008 Bergen, Norway National Centre for Macromolecular Hydrodynamics, University of Nottingham, College Road, Sutton Bonington, Nottinghamshire LE12 5RD, U.K. § ISIS Spallation Neutron Source, STFC, Rutherford Appleton Laboratory, Harwell Science and Innovation Campus, Harwell, Oxon OX11 0QX, U.K. ‡
ABSTRACT: Exploration of the molecular structure of the bacterial cell envelope informs our understanding of its role in bacterial growth. This is crucial for research into both inhibiting and promoting bacterial growth as well as fundamental studies of cell cycle control. The spatial arrangement of the lipids in the cell envelope of Gram negative bacteria in particular has attracted considerable research attention in recent years. In this mini-review, we explore advances in understanding the spatial distribution of lipids in the model Gram negative prokaryote Escherichia coli. This includes the distribution of lipids in three dimensions, (a) lateral distribution within a monolayer, (b) asymmetry between bilayers and monolayers, and (c) distribution as a function of progress through membrane division (temporal shifts). We conclude that lipid distribution in E. coli and probably all bacteria is dynamic despite a narrow lipid profile and that the biophysical properties of the membrane are inhomogeneous as a result. Finally, we suggest that further work in this field may indicate how lipid distribution is controlled and what this means for bacterial growth and metabolism and even cell cycle control.
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existence of just three lipids with an abundance of >1%, is often regarded as a model for more complicated systems such as eukaryotic membranes. Importantly, all organisms rely upon the biophysical properties of these biological amphiphiles as membrane components that self-assemble on contact with water to survive. This suggests that the biophysical role of the lipids is paramount in simpler biological systems. This idea is supported by the viability of knockout strains of E. coli. Knockout studies have shown that individually, neither CL3,18 nor PE19−21 is essential for the viability of E. coli. Furthermore, growth proceeds despite several functionally defective transporters and misfolded membrane proteins in the mutant strains lacking PE; however, such strains have an absolute requirement for divalent cations. Strains without (the anionic) CL have a considerably larger PG fraction,3,18 suggesting that the latter may replace some of the functions of the fromer. E. coli mutants without either PG or CL can grow apparently as normal below 40 °C.22,23 The phosphatidic acid (PA) fraction of strains without either PG or CL is approximately half an order of magnitude higher than that of strains that possess working PG synthases.22,23 These data
n important survival mechanism for unicellular organisms that typically live in an aqueous or damp environment is the ability to preserve the integrity of their plasma membrane (PM). Several mechanisms for achieving this have evolved. Gram positive bacteria, the type of pathogen responsible for Listeria, Clostridium, Staphylococcus, and Streptococcus poisoning, have a thick layer of peptidoglycan that protects a single bilayer.4,5 Archaea have an S-layer, similar to the peptidoglycan layer of Gram positive species, but typically comprising glycoproteins and sugar polymers.7,8 The cell wall in algae is strong because typically, its multi-layered cell wall consists of two or more of cellulose,9 sporopollenin,10 pectin,11 and xylan.12 Mycobacteria, the genus of the infectious agent that causes tuberculosis and leprosy, have a thick layer made of C60−90 fatty acids (FAs), mycolic acid, and arabinogalactan.13 Gram negative bacteria are unique in this group because they are characterized by a cell envelope that consists of a relatively thin layer of peptidoglycan between two bilayers of a dissimilar molecular profile.14−16 The metabolic machinery responsible for producing the cell envelope of Escherichia coli has received considerable research attention since the middle of the 20th Century and is now largely understood (Figure 1).17 The set of reactions responsible for producing all glyceride-based phospholipids present in E. coli, the interconversion between them and the © XXXX American Chemical Society
Received: May 27, 2016 Revised: July 22, 2016
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DOI: 10.1021/acs.biochem.6b00541 Biochemistry XXXX, XXX, XXX−XXX
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Biochemistry
curvature.25 These are analogous to the surface of a sphere, saddle and cylinder, respectively, and serve as models of the poles, septa and barrels of rod-shaped bacteria. Recent work supports the hypothesis that anionic lipids concentrate at the poles of E. coli26−30 and therefore strongly suggests a dynamic system along the longest axis of the cell, at least. There is also evidence that DNA replication relies on anionic lipids.31−33 However, it is not clear that this happens only or mainly at the poles, hinting that anionic lipids are produced or rapidly transported elsewhere. Furthermore, construction of the division plane,34 the membrane-based support for the divisome,35 also requires anionic lipids. This raises the question of whether anionic lipids are at the poles because they are produced at the division septum and become part of the poles after cytokinesis. This question has been explored using microscopy with a fluorescent dye, 10-N-nonyl acridine orange (NAO).26,28 NAO stains anionic lipids28 and may be more specific for CL26 than PG or PA. Studies using this dye have indicated that anionic lipids are indeed concentrated at the poles28 but also in domains.26,30 The existence of domains in particular suggests that CL is produced in advance of binary fission; however, it is not yet clear whether the synthesis of (the type II) CL can provide the energetic driving force for, or initiate, formation of the septum. Studies of the physical behavior of CL from E. coli suggest that it assembles into curved mesophases in the presence of a low concentration of divalent cations Mg2+ or Ca2+,19 suggesting that a locus on a curved surface is energetically favored. The evidence that CL is concentrated at the cellular poles, the most curved part of the bilayer and thus cell envelope, suggests that it is energetically favorable for them to be there. However, it is not yet clear whether the concentration of CL found in vivo confers sufficient curvature elastic stress to initiate bending of the membranes associated with formation of the division septum. The evidence that CL, and even PG, are concentrated at curved areas of the membrane implies that PE is not there or at least is only present at a lower concentration than elsewhere. This is perhaps surprising in view of PE’s well-established propensity for assembling into the inverse hexagonal phase.36 The FA profile of E. coli lipids37−39 suggests that the transition temperature of PE from E. coli to curved phases is well above the typical range of growth temperatures, though harbours stored curvature elastic stress.36 However, there is also now evidence of localization of PE to the septal area in the plasma membrane of a Gram positive bacterium. Nishibori et al. showed that Bacillus subtilis has a 2-fold enrichment of PE in developing septa in its plasma membrane.40 There is also evidence of lateral inhomogeneity of lipid distribution with the formation of domains in the PMs of both B. subtilis41 and E. coli.26,42 This is supported by evidence from biophysical studies that indicate lipid distribution is also dependent upon membrane-spanning proteins. Lipid profiling of nanodiscs from E. coli K12 strain BL21 containing the Streptomyces lividans protein KcsA by Dörr et al. has shown that the lipid profile around the protein expressed was not the same as the average.39 It contained ∼70% more CL (17 mol %) and ∼20% less PE (55 mol %) than the average (10 and 70 mol %, respectively) of the strain used, though the profile of FARs was consistent throughout.39 These data indicate that the concentration of PE, PG, and CL may vary on the lateral plane by as much as a factor of two. This range is consistent with the observation that for a bilayer to curve, one monolayer
Figure 1. Lipid metabolism in Escherichia coli. Red type indicates type II lipids and blue type anionic ones. Both PA and CL are both anionic and type II, though CL is type 0 in the absence of divalent cations Mg2+, Ca2+, and Sr2+. The three most abundant lipids are boxed. There are three genes each for synthases for PG1,2 and CL.3 The asterisk denotes the gene essential for PG synthesis.1 Abbreviations: Cls, cardiolipin synthase; pgsA, phosphatidylglycerol phosphate synthase A; pgp, phosphatidylglycerol phosphate phosphatase; psd, phosphatidylserine decarboxylase; pssA, phosphatidylserine synthase A. Adapted from ref 6.
suggest that individual lipids can be replaced with one or more others that have similar biophysical properties. This is consistent with lipids having a primarily biophysical role in E. coli and the fact that the cell cycle can proceed even without a full complement of lipids. This conclusion is supported by the evidence that mutants lacking both PE and CL are not viable,20 presumably because such cells are unable to make sufficient type II (inverted cone shaped) lipids. A similar overlap of essential functions by PE and CL has also been observed in mitochondria of Saccharomyces cerevisiae.24 Adaptability of the lipid membrane components in E. coli may be especially important for survival as expansion of the cell envelope is an absolute requirement for cell growth and division. If production of the membrane is also the limiting factor in culture growth, the cell envelope is both an excellent target for attack in controlling bacterial growth and an important consideration in attempts to promote it. The existence of two membranes in Gram negative bacteria offers two concentric barriers to the external environment and thus indicates a requirement for different physical properties. These bilayers also possess areas of greater and lower curvature that undergo changes in morphology through the cell cycle. This change in topology suggests that their lipid composition may need to adapt. The distribution of lipids in the plane of the bilayer (lateral), between monolayers or bilayers (asymmetric), and as a function of time-dependent processes like binary fission (temporal) are discussed in turn.
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LATERAL DISTRIBUTION OF LIPIDS IN MEMBRANES Lateral distribution is the arrangement of lipid species in the plane of the monolayer. This therefore includes areas of the membrane with positive, negative, and neutral Gaussian B
DOI: 10.1021/acs.biochem.6b00541 Biochemistry XXXX, XXX, XXX−XXX
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antimicrobial peptides on the inner membrane is beginning to be explored,58 and early results imply that the inner membrane is also a target for the development of antibiotics. Early evidence for the relationship between the efficacy of antibiotics and the lipid composition of the membrane showed that shifts in lipid composition had a bearing on resistance to the poreforming antibiotic polymyxin.59 More recent work has shown that modulation of lipid(s) is central to the resistance of Gram negative,60 Gram positive,61 and mycobacterial-type prokaryotes62 to this antibiotic. The distribution of Lipid A molecules in particular is important for the action of polymyxin, as these are its binding sites.63,64 However, the redistribution of lipids seems to have only limited scope for conferring resistance as the interaction is based on an electrostatic interaction of the cationic peptide with the lipid’s head group. There is now evidence of resistance based on a reduction of the anionic charge, by acylation of Lipid A.65,66 This allows Lipid A to remain on the surface of the cell envelope but reduces its efficiency as a target for polymyxin. The lantibiotic nisin works in a similar manner to polymyxin, forming a pore by docking with Lipid II67−69 through an electrostatic interaction. The abundance of Lipid II does not appear to affect nisin resistance,70 though evidence of shifts in the lipid profile of Gram positive bacteria suggests that changes in lipid composition (and, thus, distribution) may have some bearing on resistance.71 However, as the basis of the interaction between nisin and the membrane is also electrostatic and one of the central features of the activity of Lipid II in vivo is that it is translocated across a membrane,72 the scope for resistance by shifts in lipid composition is limited. The evidence that anionic charge is important for the activity of pore-forming antibiotics and that anionic phospholipids are distributed inhomogeneously both laterally and transversely suggests that there is a kinetic aspect to their production. Synthesis of lipids with respect to time is discussed next.
must adopt positive curvature (away from the water) and the other negative (towards the water) and the two fit together without producing energetically costly voids. Mass spectrometry of both eukaryotic and prokaryotic membrane proteins has shown that this technique can be used to produce a quantitative profile of the lipids associated with membrane proteins.43 The need for curvature away from the cytosol by the inner monolayer and away from the periplasm by the outer monolayer implies that the two monolayers of the PM may have different lipid compositions. Evidence of studies of lipid composition between bilayers and between monolayers is discussed next.
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ASYMMETRIC LIPID DISTRIBUTION IN MEMBRANES Early work on the molecular profile of the cell envelope of Gram negative bacteria established that it is asymmetric; the outer membrane (OM) is composed of a monolayer of lipopolysaccharide (LPS) lipids on the extra-cellular side and a monolayer dominated by PE on the periplasmic side.15 The plasma membrane’s anionic phospholipid fraction (PG and CL) is ∼18% of the total, with the outer membrane comprising ∼9% anionic lipids14,16 despite being much larger than either of the two monolayers of the PM; >98% of the remaining fraction in both the PM and the periplasmic monolayer of the OM is PE. This clear difference between bilayers and between monolayers, in the outer membrane at least, suggests that E. coli rely upon an inhomogeneous lipid distribution between monolayers as well as across them. The dissimilarity of the phospholipid profile between the inner and outer membranes in E. coli hints that lipid transport between the membranes is under active control. Free lipid transport between the inner and outer membranes has been observed for PS,44 as has fast translocation of PG and CL.45 The relatively slow movement of PE between the inner and outer membranes45 appears to be at odds with the relatively large PE fraction in the outer membrane.14,22,29 However, a higher concentration of PE in the periplasmic monolayer of the outer membrane in E. coli is consistent with PE’s behaviour as a type II lipid, which suggests that it is energetically favourable for PE to be there. There is also evidence that lipids move freely between membranes in the Gram negative bacterium Salmonella typhimurium.46 Like E. coli, the inner and outer membranes of S. typhimurium have different proportions of anionic lipids.46 This suggests that it is a common feature of all Gram negative bacteria and raises questions about the distribution of lipids within bilayers. The asymmetry of the PM in E. coli remains an important question about the lipid distribution in E. coli as the lipid composition directs the barrier properties of the membrane. It would be energetically favourable for there to be more PE on the cytosolic monolayer, due to its propensity for forming curved surfaces.47,48 Evidence of asymmetry within the plasma membrane in a Gram positive bacterium has existed for some time,49 hinting that this may also occur in E. coli; however, this has not yet been observed. This is central to the activity of antibiotics, as these drugs must either act on the membrane itself or penetrate it to work. Antibiotic activity on the outer membrane of Gram negative bacteria has received considerable attention (reviews 50−52), and links between antibiotic activity and both the lipid profile53,54 and distribution55,56 in the cell envelope have been known for some time.57 The pore forming behaviour of
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TEMPORAL CONTROL OF THE LIPID PROFILE DURING BINARY FISSION Temporal lipid synthesis describes the production of lipids linked to other cellular processes that occur periodically. For example, the vesicle budding and endocytosis in eukaryotic cells requires considerable local rearrangement of membranes that is rate-limited. Membrane rearrangements in prokaryotes are centred on binary fission, and thus, to study the lipid profile of bacteria, isolating a population of cells that are coherent with respect to the cell cycle is required. Early studies of the lipid profile in E. coli used highly mutated B/r strains. Homogenous cell populations were isolated by either centrifugation,73 new cell release,74 or cell sorting.75,76 In these studies, cells were fixed with either formaldehyde or HCl. One study verified the morphology of the cells using transmission microscopy. Each of these studies found some variation in the lipid profile through the cell cycle, though the results were not consistent with one another. It is not clear whether the method(s) for isolating cell populations or the mutated nature of the strains used accounts for this variation. A more recent study employed a drug-block approach to synchronize large populations of E. coli MG1655. This allowed them to be isolated at their most elongated (boundary of the C and D periods, equivalent to entry into the G2 phase) and where >80% were in the B period (equivalent to G1). This study showed that CL is not produced during elongation, but that PE and PG are.77 This result suggests that lipid production C
DOI: 10.1021/acs.biochem.6b00541 Biochemistry XXXX, XXX, XXX−XXX
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ACKNOWLEDGMENTS S.F. would like to thank Prof. M. R. Egmond for helpful discussions.
in E. coli is coupled to the cell cycle. Furthermore, because the cell surface area of the E. coli doubles on elongation, and the size of the CL fraction (and the percentage area of the poles) halves, these data also concur with studies that indicate CL is concentrated at the cellular poles.26,29 This in turn indicates that the DNA-dependent RNA polymerase used (rifampicin) arrests the cells before septum formation, a point at which CL is synthesized.26 A further question in this field is whether the synthesis of CL drives septal formation or is complicit with it. It is not yet clear whether the SCES produced by CL in developing septa is sufficiently strong to bend the cell envelope.
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REFERENCES
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CONCLUDING REMARKS The evidence for lipid inhomogeneity not only between bilayers, but also across the plane of the membrane (e.g., domains) and with respect to curvature and periodic cellular processes such as the cell cycle, suggests that the lipid fraction of E. coli is a more dynamic system than may have been anticipated. The dynamic nature of the lipid profile implies that the physical properties of the membranes in E. coli vary according to the cell’s needs, including in a manner that is consistent with the cell cycle. Evidence that this type of control is used in mammalian cells is also beginning to emerge,78 suggesting that it may be intrinsic to cell development. However, it is not yet known what controls the phospholipid distribution in E. coli. The most likely explanation is that the synthases that produce them are also distributed inhomogeneously, as appears to be the case in B. subtillis.40 However, it is unclear what controls the distribution of lipid-metabolizing proteins. There is scope for a role for membrane curvature in directing synthase activity, though this fails to explain how CL synthase at or CL transport to the septal area occurs. Much of the research into the control of the distribution of lipids has so far focused on the lipid translocators involved in preparation of the cell wall,72,79,80 though evidence about the transport of phospholipids is beginning to emerge.80,81 Techniques are being developed that could be used to probe phospholipid transport more closely,82,83 though a complete understanding has yet to be constructed. Further work is also required to determine both the distribution of lipid synthases and their expression. Such work will inform our understanding of how lipid distribution is controlled. This in turn may lead to studies that can test whether expansion and remodelling of the cell envelope is the central control mechanism for bacterial growth, as temporal studies have hinted.77 Understanding of these mechanisms may be used to support both the development of novel antibiotics, but also industrial fermentation and as a model for developing hypotheses about the lipid distribution and metabolism in higher organisms.
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AUTHOR INFORMATION
Corresponding Author
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[email protected]. Funding
S.F. is funded by Forskningsrådet and the Universitetet i Bergen. D.J.S. is funded by the RCaH and the University of Nottingham. Notes
The authors declare no competing financial interest. D
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Current Topic
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DOI: 10.1021/acs.biochem.6b00541 Biochemistry XXXX, XXX, XXX−XXX
Current Topic
Biochemistry
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