Available online at www.sciencedirect.com
ScienceDirect
Prokaryotic cell division: flexible and diverse
Tanneke den Blaauwen
Gram-negative rod-shaped bacteria have different approaches
to position the cell division initiating Z-ring at the correct
moment in their cell division cycle. The subsequent maturation
into a functional division machine occurs in vastly different
species in two steps with appreciable time in between these.
The function of this time delay is unclear, but may partly be
explained by competition for Lipid-II between proteins involved
in length growth that interact directly with the Z-ring early in the
maturation phase and the proteins involved in septum
synthesis. A second possible activity of the early Z-ring might
be the monitoring of or the active involvement in DNA
segregation through proteins such as ZapA and ZapB/MatP
and their homologues.
Addresses
Bacterial Cell Biology, Swammerdam Institute for Life Sciences,
University of Amsterdam, Science Park 904, 1098 XH Amsterdam, The
Netherlands
Corresponding author: den Blaauwen, Tanneke ([email protected])
Current Opinion in Microbiology 2013, 16:738–744
This review comes from a themed issue on Growth and development:
prokaryotes
Edited by Thomas G Bernhardt and Waldemar Vollmer
For a complete overview see the Issue and the Editorial
Available online 28th September 2013
1369-5274/$ – see front matter, # 2013 Elsevier Ltd. All rights
reserved.
http://dx.doi.org/10.1016/j.mib.2013.09.002
Introduction
Escherichia coli has been the dominant Gram-negative
organism to study cell division and its mode of division
has therefore become the default. The increased
genetic accessibility, cultivability of bacterial species
and the fluorescent protein revolution have given access
to other organisms that show quite some variation in
their approach to binary fission. From these studies the
question emerges whether the variation concerns only
the preparation for division or also the core of the
molecular mechanism. Cell division in E. coli is initiated
by the polymerization of the tubulin homolog FtsZ in a
ring-like structure at mid cell. This ring recruits the
proteins that are required for the synthesis of the septum
during division. Binary fission requires the cell to define
its middle, to know when to initiate division and to
regulate the concerted invagination of the envelope
with timely segregation of the chromosomes. This
review discusses the various solutions Gram-negative
Current Opinion in Microbiology 2013, 16:738–744
(and some Gram-positive) species have found to reliably
handle these three problems.
Spatial regulation of the Z-ring
Negative regulation
The polymerization of the tubulin homologue FtsZ at
midcell in rod-shaped bacteria is thus far recognized as
the first step in the initiation of binary fission. The
polymers assemble into a ring-like structure that will
guide the cell envelope synthetic machinery during the
synthesis of the septum to create two new cell poles. The
concentration of FtsZ molecules in the gamma-proteobacterium Escherichia coli is on average 4.5 mM [1,2]. With
a critical concentration for polymerization of 1–2 mM [3],
the polymerization of FtsZ has to be inhibited continuously and everywhere in the cell until the cell is ready to
divide. This is achieved by the combined action of the
Min system, which inhibits polar Z-ring formation and by
the nucleoid occlusion system that prevents the formation
of FtsZ polymers near the nucleoids. The Min system
consists of the FtsZ inhibitor MinC [4], which is bound to
the cytoplasmic membrane by the ATPase MinD. In the
ATP bound form MinD dimerizes and binds cooperatively to the cytoplasmic membrane with an amphipathic
helix, whereas in the ADP bound form, MinD is cytoplasmic. The third protein of the min system, MinE is
also associated with the cytoplasmic membrane and
stimulates the ATPase activity of MinD forcing it to
release from the membrane [5]. The MinCD concentration is highest at one of the cell poles. Consequently,
their release causes movement of the min proteins to the
opposite cell pole during which MinD exchanges ADP for
ATP and binds again cooperatively to this cell pole. The
MinE stimulated release of MinCD from this pole causes
subsequently the opposite movement, which results in an
oscillation of the MinCD proteins between the two poles
of the cell every 20–50 s [6–9] (Figure 1A). Consequently,
FtsZ cannot establish a stable Z-ring close to the cell
poles. In the absence of the Min system, FtsZ is able to
form polar Z-rings and DNA-less mini cells are produced.
Two mechanisms could contribute to the nucleoid occlusion effect. The first is an active enzymatically regulated
mechanism. SlmA is a TetR-like DNA binding protein
with approximately 50 binding sites regularly distributed
on the chromosome with the exception of a region flanking the DNA replication terminus called the Ter macrodomain [10,11]. The SlmA dimer interacts with helices on
the surface exposed face of the FtsZ C-terminal domain
blocking higher ordered structures but not protofilament
formation [10,12]. SlmA binds to DNA as a dimer of
dimers and can spread over the DNA preventing FtsZ
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Prokaryotic cell division: flexible or diverse den Blaauwen 739
Figure 1
(a)
MinE
D1
ParB/S
MinCD
-
+
FtsZ
holdfast
+
TipN
MipZ
+
+
D2
-
ParA
oscillating Min system
nucleoid
(b)
stalked
cell
D3
and nucleoid occlusion
-
-
-
MipZ gradient, FtsZ displaced
-
+
-
(c)
flagellum
D4
ZapAB
+
-
MatP
segregation registration
Current Opinion in Microbiology
Prevention of premature polymerization of FtsZ into the division ring. (A) In E. coli MinC (red) inhibits FtsZ polymerization. MinD (red) is bound to the
membrane in the ATP bound state and recruits MinC. MinE (purple band) binds to the membrane upon interaction with MinD and stimulates the
ATPase activity of MinD causing its release from the membrane and concomitantly that of MinC [5]. Because of the absence of MinCD in the other
half of the cell, the proteins diffuse to the opposite pole. On its way MinD loads an ATP molecule, which allows the protein to dimerize, collect minC,
and bind to the membrane of the opposite pole. Here, the MinE stimulated release starts again. As a results the Min proteins oscillate from one pole to
the other inhibiting FtsZ polymerization everywhere until the cell has reached sufficient length to have a non-inhibitory MinC concentration at mid cell.
The Min oscillation is probably one of the most computer-simulated bacterial systems known [8,9]. (B) The nucleoid (grey) inhibits the formation of
higher order FtsZ structures because of the presence of an oligomeric configuration of SlmA proteins bound to the DNA as a dimer of dimers [10–
13,14]. (C) Because SlmA has no DNA binding sites in the chromosomal Ter macrodomain, the Z-ring can be formed over chromosomes that are not
completely segregated. The binding of ZapA and ZapB (green) to the Z-ring facilitates their interaction with the chromosomal Ter macrodomain
condensing protein MatP (yellow) [55,56]. The Z-ring is either able to sense the status of chromosome segregation through ZapB or ZapB might be
actively involved in DNA segregation one way or another. (D1) In C. crescentus the origin of DNA replication is bound to the stalked pole by ParB/parS
(blue). The FtsZ inhibiting protein MipZ (green) binds as well to DNA as to ParB. Here, a gradient from ParB extending over the nucleoid is formed
because the ATP-bound dimeric form of MipZ has a higher affinity for DNA than for ParB whereas the ADP-bound monomeric form of MipZ has a
higher affinity for ParB. [25]. (D2) When the DNA origins are replicated, the new origin and new ParB/parS are pulled towards the flagellar pole by
ParA polymers bound to the TipN protein (black) [22,23]. (D3) This causes MipZ to be distributed in a gradient in the cell that is highest at the poles and
lowest at the division site like the Min proteins in E. coli. MipZ displaces FtsZ (orange) still present from the previous division in the non-stalked pole.
(D4) When the cell has reached sufficient length to have a local minimum of MipZ proteins and the FtsZ gene is duplicated and methylated [26], which
allows the synthesis of new FtsZ proteins, a Z-ring can be formed.
protofilament association [13,14]. The second, passively
regulated mechanism might involve cotranslational translocation of proteins across the cytoplasmic membrane
[15]. About 30% of E. coli proteins have an envelope
destination and the crowded continuum between the
chromosome, mRNA, and the protein translocon might
physically block stable FtsZ polymer formation. However, at the moment no conclusive experimental evidence
is available to validate this hypothesis. In conclusion, the
Z-ring will not be formed at mid cell until the cell has
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reached a length where the Min proteins concentration is
sufficiently low at mid cell to allow FtsZ polymerization
and the nucleoids have been segregated to an extend that
only the chromosomal Ter macrodomains remain at mid
cell.
The equally well-investigated Gram-positive rod-shaped
bacterium Bacillus subtilis has a non-oscillating Min system consisting of the MinC, MinD, MinJ and DivIVA
proteins. B. subtilis first synthesizes a new septum, which
Current Opinion in Microbiology 2013, 16:738–744
740 Growth and development: prokaryotes
is cleaved at a later point in the cell cycle. The DivIVA
protein is a curvature sensitive membrane protein [16,17]
that binds to the old cell poles and the new septa. MinJ
recruits MinC and MinD to DivIVA, where MinC prevents additional Z-ring formation. Cleavage of the septum causes the collapse of the DivIVA structure in a
number of patches, which are still sufficient to prevent Zring formation near these poles [18]. The NOC protein
[19], which is not homologous to SlmA, is responsible for
nucleoid occlusion. Like SlmA, its DNA binding sites are
dispersed over the chromosome but absent from the Terdomain [20]. Thus far it has not been possible to detect a
direct interaction of NOC with FtsZ suggesting that it
inhibits division by another mechanism than SlmA [21].
An inhibitive gradient-nucleoid occlusion all-in-one system has evolved in the alpha-proteobacterium Caulobacter
crescentus. Its nucleoid is bound to the stalk pole by ParB
that binds to parS DNA sequences in the vicinity of the
origin of replication [22,23]. MipZ is a MinD-type
ATPase that binds DNA nonspecifically as a dimer in
the ATP bound state and that also interacts with ParB
[24]. Upon DNA replication, the new origin of replication
is segregated actively by ParA that polymerizes between
the new ParB/parS origin regions and the TipN protein
attached to the opposite or flagellar cell pole of the
crescent-shaped cell [22,23] (Figure 1D). In this process
MipZ is pulled along to the flagellar cell pole where it
displaces FtsZ, which has remained at this poll since the
previous division. As a result both poles are now occupied
by the FtsZ polymerization inhibiting MipZ, which
leaves the mid cell position free for the assemblage of
the Z-ring provided that the nucleoids are sufficiently
segregated to have a minimal MipZ concentration at mid
cell [25]. Additionally, by coupling the expression of
FtsZ and MipZ to the full methylation state of the
promoter region of their genes, their expression is coordinated with chromosome replication [26].
Positive regulation
The rod-shaped delta-proteobacterium Myxococcus
xanthus has opted for a system that positively regulates
the formation of the Z-ring at mid cell using again a
MinD-like ATPase; PomZ [27]. PomZ localizes to the
future site of division before FtsZ and is assumed to
recruit FtsZ via another unidentified protein. Although
the GTPase activity of purified M. xanthus FtsZ could be
measured, FtsZ polymers have not been described in the
literature. Therefore, protofilament formation of detectible length might require a positive regulator in M.
xanthus. Positive regulation of FtsZ ring formation has
been reported for some Gram-positive species as well
[28,29]. Recently, a rod-shaped Gram negative gammaproteobacterium that lives in symbiosis with the
nematode Laxus oneistus has been described to divide
longitudinal instead of transverse [30]. The young nondividing cells of this sulfur-oxidizing marine bacterium
Current Opinion in Microbiology 2013, 16:738–744
were shown to contain hardly any FtsZ, whereas the
dividing cells showed a clear Z-ellipsoid along their
length axes (Figure 2C). This might therefore be another
example of positive Z-ring regulation.
Sloppy positioning
Many Gram-negative bacteria position their Z-ring very
precisely. For instance, E. coli positions its septum at
50 3% (N.O.E. Vischer and T. den Blaauwen, unpublished) of its cell length and C. crescentus positions the
division site slightly off mid cell at 53.7 0.1% [23]) of its
cell length. The helix-shaped epsilon-proteobacterium
Helicobacter pyloris positions its Z-ring with very little
precision [31] and might correct for difference in daughter
cells size by regulating growth speed of the individual
daughter cells, as does Mycobacterium tuberculosis [32,33]
and Corynebacterium glutamicum [34] that position their Zring in the 25–75% region of their cell length.
In conclusion, multiple mechanisms exist that lead to a
satisfactory Z-ring positioning. Is this diversity propagated in the maturation of the division machinery and
in the molecular mechanism to synthesize the septum or
do all routes converge to the same mechanism?
Timing of the assembly of the division protein
complex
Division requires the participation of a large number of
proteins that are collectively termed the divisome. These
proteins can be functionally discriminated in Z-ring organizing proteins, proteins involved in peptidoglycan construction and regulatory proteins with a less clear function.
The timing in the cell division cycle of the mid cell
localization of divisome proteins has been investigated in
E. coli, either by synchronization [1] or by growing cells such
that their cell age can be related to cell length [35,36]
(Figure 2A). In C. crescentus cell age can be determined by
synchronization of the cell division cycle (Figure 2B) and in
the rod-shaped Gram-positive Bacillus subtilis by timelapse
movies of out growing spores [37]. Alternatively, for the
American football-shaped Gram-positive Streptococcus pneumonia cell age is deduced from cell size selection after
imaging of the cells [38,39]. In the four very unrelated
species investigated, the assembly of the division machinery occurs in at least two distinct time-separated steps. One
is the polymerization of the FtsZ-ring with a number of Zring associated proteins such as FtsA, ZipA, ZapA, ZapB,
and EzrA. About 20% of the cell cycle later the proteins that
are associated with septum synthesis such as the FtsQLB
complex, FtsK, PBPs, FtsW, and FtsN localize. Apparently,
a broad consensus exists about the necessity for timeseparated assembly of the division machinery.
Interaction between the proteins responsible
for elongation and cell division
Evidence is accumulating that proteins, which are normally involved in cell elongation, assemble at mid cell in
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Prokaryotic cell division: flexible or diverse den Blaauwen 741
Figure 2
(a)
100/0%
(b)
19-30%
80%
40-55%
60%
100%
swarmer
cell
20%
Escherichia coli
holdfast
25-38%
stalked
cell
60%
flagellum
48-52%
Caulobacter crecentus
(c)
?
Laxus oneistus symbiont
Current Opinion in Microbiology
The cell division cycle of three gram-negative species with different approaches to cell division are schematically presented. (A) In the gammaproteobacterium E. coli the Z-ring (orange circle) is formed at about 25–38% of a division cycle of 85 min. Between 48 and 52% of the cycle the
majority of the proteins involved in septum synthesis and coordination of the invagination of the three layered cell envelope have arrived at mid cell
(purple circle) and at 60% a clear beginning of a constriction can be discriminated by phase contrast microscopy [1,35,36]. (B) The alphaproteobacterium C. crescentus has a free-living form, the swarmer cell, and a sessile-form the stalked cell. During a division cycle of 120 min the Z-ring
and associated proteins localize at the division site between 19 and 30% of the cycle and the septum synthesizing proteins localize between 40 and
55%. Division commences at 60% of the division cycle [41]. (C) The Laxus oneistus symbiotic gamma-proteobacterium stands with one pole on the
epidermis of the marine nematode and growths in width. At an unknown point in its division cycle it places a Z-ring along its length axes and divides
longitudinally to ensure that each of the two daughter cells will bind to the worm [30]. It is not known whether these bacteria show a similar delay in
divisome maturation as the other two species in this figure.
close association with the Z-ring formation. In E. coli, the
actin homologue MreB that recruits the proteins involved
in elongation, the peptidoglycan transpeptidase PBP2
and the lipid-II synthase MurG localize at mid cell before
the Z-ring is fully established [35,40]. In C. crescentus
FtsZ localization is followed by MreB and MurG and the
Z-ring associated proteins [41,42]. In the absence of the
late localizing cell division proteins, such as the FtsQLB
complex [43], the PBP3FtsW complex [44] and FtsN, E.
coli synthesizes a band of peptidoglycan at the position of
the Z-ring [45] whereas C. crescentus synthesizes a much
broader band of new peptidoglycan [46]. Since the Z-ring
cannot synthesize peptidoglycan, a logical function for
the mid cell localization of MreB, PBP2 and MurG, would
be the synthesis of a band of so-called ‘preseptal’ peptidoglycan or PIPS [45,47]. Curiously, PIPS has been
shown to be present in cells that lack almost all known
proteins involved in peptidoglycan synthesis or hydrolysis
including the MreBCD proteins and only FtsZ, ZipA and
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either PBP1a or PBP1b and possibly PBP2 were required
[48]. Interestingly, in the presence of an MreB mutant
that is not able to interact with FtsZ but that is functional
in elongation, a mature divisome is formed that is not able
to synthesize peptidoglycan [40]. Another function of the
presence of the elongation proteins at mid cell could be
the positioning of the Lipid-II synthesizing protein complex [42,49] and possibly the bifunctional class A PBPs.
The presence of Lipid-II and a band of newly synthesized
peptidoglycan could attract the protein complex required
for septal peptidoglycan synthesis leading to the functional maturation of the division machinery. PBPs of
several bacterial species localize/delocalize because of
the presence/absence of their substrate [35,50,51,52].
Function of two-step assemblage of the
division machinery
At least three rod-shaped and one American footballshaped bacterial species are known to mature their
Current Opinion in Microbiology 2013, 16:738–744
742 Growth and development: prokaryotes
divisome in two clearly separated steps in time. What is
the purpose of this delay? It seems unlikely that this time
period is required to synthesize preseptal peptidoglycan,
since C. crescentus and E. coli synthesize vastly different
amounts of preseptal peptidoglycan during this delay in
divisome assembly. One additional function might be to
contribute to chromosome segregation into the two
daughter cells to prevent their bisection by cell division.
In Enterobacteriaceae and Vibrionaceae species, ZapA
and ZapB have, apart from their putative Z-ring stabilizing function [53,54], at least a second and potentially
much more important function: The Ter macrodomain in
these species is compacted by MatP that binds to approximately 23 matS sequences in this chromosome region
[55,56]. During DNA replication and segregation, the
termini of the E. coli chromosomes end up in the middle
of the cell. ZapA recruits ZapB to the Z-ring, where ZapB
is able to interact with MatP and respond to the status of
DNA segregation [57].
Although detailed information of many bacterial species is
lacking, the present knowledge of bacterial cell division
suggests that many roads lead to a satisfactory positioning of
the Z-ring. The next step towards maturation of the division
machinery seems to be more conserved and requires communication between the elongasome and the Z-ring, preseptal peptidoglycan synthesis and a chromosome
segregation (monitoring) system. Further research on the
diversity of bacterial species will help to disentangle local
variation from the core business of binary fission.
Acknowledgements
This work was supported by the DIVINOCELL project of the European
Commission (FP7-Health-2007-B-223431). I thank Leendert Hamoen for
critically reading the manuscript.
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MreB and PBP2 are shown to localize simultaneously at mid cell together
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An excellent detailed study on the timing of the localization of many
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A thorough attempt to find out which proteins are needed for preseptal
peptidoglycan synthesis or PIPS and in conflict with (33), which can
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Current Opinion in Microbiology 2013, 16:738–744
744 Growth and development: prokaryotes
55. Mercier R, Petit M-A, Schbath S, Robin S, Karoui El M, Boccard F,
Espéli O: The MatP/matS site-specific system organizes the
terminus region of the E. coli chromosome into a
macrodomain. Cell 2008, 135:475-485.
56. Dupaigne P, Tonthat NK, Espeli O, Whitfill T, Boccard F,
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Crystal structures of MatP-matS complexes show that the tetrameric
MatP can crosslink distant matS sequences on the chromosomal Ter
macro-domain.
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The terminus of DNA replication is positioned at mid cell. The MatP
protein condenses the regions flanking the terminus (Ter macrodomain)
by binding to matS sequences in this domain. MatP binds ZapB only
when ZapB is bound to ZapA at the Z-ring. This is the second connection
between division and DNA segregation, the first being the deconcatenation of the chromosomes by the divisome protein FtsK in combination
with Xer recombinases.
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