Doi:10.1016/j.tim.2005.10.00

TRENDS in Microbiology Vol.13 No.12 December 2005 Towards a comprehensive viewof the bacterial cell wall Boris Dmitriev1, Filip Toukach2 and Stefan Ehlers3 1N.F. Gamaleya Institute for Epidemiology and Microbiology, Gamaleya str. 18, Moscow 123098, Russia2N.D. Zelinsky Institute for Organic Chemistry, Leninsky Prosp. 33, Moscow 119991, Russia3Division of Molecular Infection Biology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany Direct in vivo visualization, in full atomic detail, of the different concept for the architecture of bacterial cell microbial cell wall and its stress-bearing structural walls, known as the scaffold model As a result of re- architecture remains one of the prime challenges in evaluating experimental evidence, this model shows microbiology. In the meantime, molecular modeling can glycan chains within murein of either Gram-negative or provide a framework for explaining and predicting Gram-positive bacteria running perpendicular to the mechanisms involved in morphogenesis, bacterial cell plasma membrane. Cross-linked by peptide bridges, they growth and cell division, during which the wall and its produce a continuous sponge-like matrix (not layers) that major structural component – murein – have to protect can function as an elastic external cytoskeleton.
the cell from osmotic pressure and multiple tensile Obviously, the traditional and novel models are forces. Here, we illustrate why the scaffold concept of mutually exclusive. However, because the chemical murein architecture provides a more comprehensive parameters of the two models are closely related, and representation of bacterial cell wall physiology than because there is no direct experimental approach to previous models.
distinguish between them, a stimulating, if controversial,discussion of the two models has been initiated in theliterature In our opinion, it is time to put themodels to use for explaining and predicting basic facets of bacterial cell physiology. Here, we show how the scaffold The cell wall of bacteria represents a structural unity of model fulfills this demand in the paradigmatic case of variable thickness, which is located outside the plasma Gram-negative Escherichia coli.
membrane and completely covers the cell. It is both firm-to-rupture and elastic, thereby preventing the cell fromdisintegration by the intracellular osmotic pressure .
The major stress-bearing component of the bacterial Murein determines the shape of the bacterial cell.
cell wall is murein, a chemical synonym of which is Although intuitively evident for symmetrical cells that peptidoglycan (PG). In 1964, Weidel and Pelzer possess a classical (round or rod-like) morphology, this proposed that PG strands within the ‘bag-shaped' murein statement must also be true for the branched type of (sacculus) run parallel to the plasma membrane. Being morphology, when cells exhibit Y-, X- or H-like shapes cross-linked by peptide bridges, glycan chains were caused by mutations of specific genes encoding the thought to make thin networks (layers). Glycan chains synthesis of murein-assembling enzymes. The morpho- were assumed to run perpendicular to the long axis of the logical transformations observed for the rod-like E. coli cell, whereas peptide bridges were arranged in parallel cells are particularly impressive: after a set of The major obstacle for direct experimental proof of mutations they grew either as filaments or branched this postulated structure is that a living cell does not dendrites or large spheres, the spheres dividing like possess a fixed cell-wall structure because the cell wall is Neisseria or Staphylococcus (i.e. with a successive in a state of permanent biosynthesis, assembly, disas- alteration of the division plane orientation). These radical sembly and turnover. This makes the cell-wall architec- morphological transformations are solely possible if the ture of each individual cell within a population both stress-bearing murein possesses a kind of universal heterogeneous and irregular.
tertiary structure, which effortlessly tolerates and enables During the past four decades, several experimental major morphological perturbations. The major structural observations have accumulated that tend to contradict the principle of murein architecture has to be universal and adopted structural paradigm of PG layers (reviewed in valid for all types of bacterial cell morphology.
). It is, therefore, timely and necessary to readdress thecrucial question of how the murein tertiary structure General chemical and physical principles of murein copes in vivo with the major processes and tensile forces of bacterial cell physiology. Recently, we proposed a radically Although the primary chemical structure of murein mightvary in different organisms, the material, regardless of the Corresponding author: Ehlers, S. ([email protected]).
Available online 19 October 2005 taxonomy and morphology of a given bacterial cell, 0966-842X/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tim.2005.10.001 TRENDS in Microbiology Vol.13 No.12 December 2005 The predominant occurrence of short chains translates Box 1. Characteristic structural elements of murein into numerous cuttings within the network. The number (i) A peptidoglycan (PG) strand is both a regular and symmetrical of large holes increases dramatically when the degree of molecule. Every strand consists of alternating disaccharide-peptide murein cross-linking is reduced to the levels observed in units; disaccharide fragments are connected into regular glycan nature, and in this case the network becomes dysfunc- chains, and peptide substituents project outward from each oddmonosaccharide residue The disaccharide-repeating unit consists of N-acetylmuramic acid (blue disk, beginning of the The situation is radically different in the case of the chain) and N-acetylglucosamine (red disk).
scaffold model, which does not crucially depend on the (ii) According to X-ray diffraction data, conformation of the strand strand lengths and readily accommodates both the short represents a right-handed helix with the symmetry order C4, each chains and a lower degree of cross-linking (The turn of the helix consisting of four disaccharide units with fourpeptide side-chains oriented outward A strand with two crucial questions are: (i) how are the glycan strands turns of the helix is shown in the insert.
oriented relative to the plasma membrane and each other (iii) Strands are of different lengths: oligomers comprising 8–12 and (ii) what is the murein architecture like? disaccharide units predominate but short chains and longpolymers are also present.
Structural paradigm for murein architecture in rod-like (iv) The formation of peptide bridges is readily possible because each peptide arm possesses both free amino (filled circles) and Gram-negative bacteria carboxyl (empty circles) groups.
The murein of all Gram-negative bacteria belongs to the (v) Not all adjacent peptides are bridged, therefore, the degree of simplest chemical type The cell wall of E. coli has cross-linking is variable.
been studied comprehensively by electron microscopy and (vi) Some crucial physical parameters are as follows: the length and the width of one disaccharide unit is 1.0 and 1.1 nm, respectively biochemical methods. The actual distance between the the lengths of the peptide arm and the expanded bridge are 2.2 inner and outer membranes (i.e. the periplasm height in and 4.36 nm, respectively hydrated E. coli cells deeply frozen at ambient pressure)was reproducibly measured as 33 nm . Furthermore,the observed width of the major murein body was 8 nm,and the material was located close to the outer membrane.
Here, it was centered around the ends of the peptidemoieties of lipoprotein molecules, whose protein core is8 nm The bulk of murein extended toward the plasmamembrane and gradually became less dense; the overallthickness of the whole murein mass was w18 nm Evidently, this material is a major structural component ofthe periplasm and represents the resilient ‘periplasmicgel' of the bacterial envelope Combining the principles of the scaffold-like murein architecture and the experimentally determined par-ameters of the E. coli periplasm detailed previously, wenow present the first graphical in-scale depiction of theGram-negative envelope (Traditional cartoonsof the Gram-negative envelope depict the periplasmic TRENDS in Microbiology space as essentially empty with a thin murein layer insidetherefore, our presentation in is Figure I. General view of a separate peptidoglycan (PG) strand.
radically different from all previous models. however, readily illustrates that the periplasmic space isprone to compression. It is therefore easy to understand invariably comprises PG strands cross-linked by peptide that, when E. coli cells were rapidly frozen at a high bridges The chemical features of PG strands are pressure, the height of the periplasm dropped to 20 nm and the visible zone of murein was reduced to 6 nm .
The murein sacculus is a cocoon-like construction, The murein architecture resembles a sponge-like which has to contain and oppose the rupturing forces, matrix, the height of the matrix being proportional to therefore, its architecture must correspond to the mech- the glycan-chain lengths. How can the scaffold-like anical principles of safe engineering and constructing.
murein architecture be assembled during continuous Therefore, stress-bearing elements within murein of the bacterial cell growth and division? There are two rod-like bacterium must be arranged differently than peculiarities that compound this problem: (i) the murein- suggested by the classical model and, if we remain within assembling enzymes are membrane-bound proteins that the confines of this model, these elements should adopt a use precursors from the cytoplasm, and (ii) the wall, which hexagonal architecture (Analogous consider- is being assembled, is located in the periplasm at a ations have led Koch to propose the term ‘chicken-wire' substantial distance from the membrane. Before answer- network It is clear that the stress-bearing properties ing the question, we would like readers to recall that of the ‘chicken-wire' architecture directly depend on the cylindrical and pole regions of the rod-like cell are lengths of PG-strands. These, however, have been synthesized by two distinct mechanisms: (i) patch- demonstrated experimentally to be rather short .
insertion mode of growth and (ii) zonal mode of growth

TRENDS in Microbiology Vol.13 No.12 December 2005 Figure 1. Arrangement of the stress-bearing elements within the cell wall of a rod-like bacterium. (a) Glycan chains run as postulated by the classical model, that is, parallel tothe plasma membrane and the short axis of the cell (not along the tensile forces). Transformation to the ‘chicken-wire' architecture is most probable. (b) Glycan chains arearranged perpendicular to the plasma membrane, peptide bridges being the stress-bearing elements of the construction (scaffold model). The orientation of bridges is inaccord with the direction of tensile forces. A small fragment of the murein architecture is enlarged in the circle. Nine cross-linked peptidoglycan (PG) strands are clearly seen,plasma membrane (IM) being underneath the strands. For the purpose of clarity, only one turn of each strand is depicted, otherwise numerous crossed lines obscure thepicture. In fact, strands are longer and the number of bridges is bigger. Four helical pores (channels) are seen round the central strand.
via attachment of the nascent strands to the leading edge patchiness of murein en masse insertions into the sidewall of E. coli To explain the mode of cylindrical growth, the concept Regarding a secure mechanism for cell-wall division, of membrane-adhesion zones developed by Bayer is we propose that, after chromosome segregation, intensive appropriate . According to this concept, the inner synthesis of murein is triggered, culminating in septum membrane (IM) is able to bulge and approach the outer formation. During the constriction of the cell, the leading membrane (OM), effectively making a kind of OM– edge of the murein structure and the curved bend of murein–IM multi-enzyme complex The initial local the plasma membrane are clearly exposed, both of them hollow space within the murein can be produced, for adopting the form of concentric rings. The septum grows example, by the soluble transglycosylase Slt70 and strictly centripetally, like the iris diaphragm of a camera, endopeptidase; both enzymes are known to participate from the peripheral edges of the murein to the center in gradual murein degradation . The cavity is In the case of septum formation, the murein-synthesizing expected to expand by the turgor pressure, thus complexes, such as the members of FtsZ-ring and enabling the inner membrane to bulge. If the murein- associated counterparts , are probably located not at the top of membrane bulges (as is the case for cylindrical protrusion, they can simultaneously use precursors growth) but at the invaginated membrane curve.
coming from the cytoplasm and be in contact with the The proposed concept of bacterial cell-wall morphogen- pre-existing murein, which functions as the acceptor for esis is in agreement with well-documented observations the nascent strands. As the newly synthesized murein that the process of a gradual E. coli cells lysis is paralleled starts to fill the expanded cavity, the convex membrane by the release of simple muropeptides and peptides with gradually returns to its original position. As soon as the concomitant increase in the cross-linking index of the perforated murein is mended and a large piece of new remaining cell walls Moreover, in the course of lysis, material is inserted, the current round of murein growth walls become progressively thinner from inside to outside is completed and the inner membrane bulges appear whereas no visible holes and long cuts were observed in other places to repeat new cycles. Metaphorically on the isolated sacculi . It is clear from that speaking, the membrane loaded with the murein- lytic degradation of the murein from inside by Slt70 and synthesizing complexes functions as a sewing machine, endopeptidase will result in the release of simple new murein being assembled in a direction from the OM degradation products, and the surviving walls become to the IM To the best of our knowledge, this thinner but relatively more cross-linked in comparison to is the only mechanism that explains the random the original murein. It is difficult to explain these TRENDS in Microbiology Vol.13 No.12 December 2005 Highly cross-linked zone Murein precursors Newly synthesized TRENDS in Microbiology Figure 2. Proposed molecular architecture of a Gram-negative envelope and a tentative mechanism of bacterial cell wall growth. (a) The asymmetric outer membrane (OM)consists of two leaflets, the external one comprising lipopolysaccharide molecules (blue) and the internal leaflet comprising phospholipids (green). The essential componentof the internal leaflet is lipoprotein (brown), the peptide moiety of which protrudes into the periplasm. Different transmembrane porins, either trimeric or monomeric, arecommon components of the OM. The inner membrane (IM, green) comprises phospholipids and is penetrated by different transmembrane proteins, of which two permeasesare presented (black serpentine). Permeases are thought to locate strictly beneath the corresponding porins. The major component of the periplasm is the hydrated‘periplasmic gel'(blue diffuse zone) consisting of murein, the bridged PG strands of which run perpendicular to the IM. Certain central bridges are covalently connected to theends of lipoprotein molecules that protrude into the periplasm. The height of the periplasm is variable and depends on external conditions. (b) Dynamics of the lateral mureingrowth by the patch-insertion mechanism is clearly seen from two ‘snap-shot' pictures. On the left, the plasma membrane locally bulges to fill the cavity produced within theold cell-wall by a lytic enzyme bound to the periplasm. The existing turgor pressure is a driving force for both the cavity expansion and membrane bulging. The murein-synthesizing complexes (MSC ovals) locate on the bulge top, therefore having the possibility of translocating the biosynthetic murein precursors from the cytoplasm acrossthe membrane with concomitant synthesis of the novel PG strands and their immediate attachment to the old wall edges. On the right, the novel murein patch is growing byelongation of the inserted strands, thus filling the cavity and pushing the membrane bulge downward until the plasma membrane returns to its original state.
TRENDS in Microbiology Vol.13 No.12 December 2005 Table 1. Experimental observations and murein models: compatibility Observation and properties Arrangement of the strands and peptide bridges Conflict (classical), Agreement (chicken-wire) along tensile forcesBranched-cell morphology Successive alteration of the division plane orientationRelease of 100-kDa proteins by hypo-osmotic shockIn silico modeling of murein assembly from separate strands to form stress-bearing matrixReduction by 50% of murein content per unit of observations from the position of the classical model gradients being built up within the murein. The existence because it implies that the cell wall is already thin and of both the compartmentalization and the gradient of that lytic enzymes cut it along the glycan strands, much electrical potential is a prerequisite for the effective influx like scissors cut paper.
of necessary nutrients across the periplasm; this is alsotrue for the trafficking of polymers via distinct secretionpathways. These features of the proposed murein archi- Current status of the scaffold model tecture offer new links to further biophysical and We have also tentatively simulated the layered murein biochemical studies of the functions of bacterial cytoplasm architecture according to the traditional network-model, and envelope, particularly those high-resolution technol- and a comparison of the two models is presented in ogies that are aimed at unravelling the problem of how . Although the scaffold concept seems to have clear cells are able to control precisely both the predetermined advantages over the traditional model, we do not wish to form and the constancy in length and width of their imply that it is unconditionally superior. Repeated experimental feedback and modeling input from cell wallexperts of divergent opinions will be necessary to refine the model to fully reflect reality.
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