Blackwell Science, LtdOxford, UKMMIMolecular Microbiology0950-382XBlackwell Publishing Ltd, 2004? 2004543588597Review ArticleThe septal ringD. S.

Weiss

Molecular Microbiology (2004) 54(3), 588–597 doi:10.1111/j.1365-2958.2004.04283.x

MicroReview

Bacterial cell division and the septal ring

David S. Weiss* answering this question is to identify protein–protein inter-

Department of Microbiology, University of Iowa, Iowa City, actions among the division proteins. I will summarize what
IA 52242, USA. is known about this topic and suggest reasons why
progress has been slow. (ii) How does FtsZ drive cytoki-
nesis? Although the answer remains elusive, recent
Summary
experiments suggest the rate-limiting step in turnover of
Cell division in bacteria is mediated by the septal ring, the FtsZ polymer is GTP hydrolysis. I will speculate on the
a collection of about a dozen (known) proteins that implications that this has for the ability of FtsZ to generate
localize to the division site, where they direct assem- force. (iii) How is septum assembly coordinated with par-
bly of the division septum. The foundation of the sep- titioning of chromosomes to daughter cells? At least three
tal ring is a polymer of the tubulin-like protein FtsZ. mechanisms by which FtsK prevents the septum from
Recently, experiments using fluorescence recovery closing on the chromosomes like a guillotine have been
after photobleaching have revealed that the Z ring is elucidated. I will describe these activities, and briefly com-
extremely dynamic. FtsZ subunits exchange in and pare FtsK with a similar protein, SpoIIIE, involved in
out of the ring on a time scale of seconds even while sporulation in Bacillus subtilis. (iv) How are daughter cells
the overall morphology of the ring appears static. separated? Two peptidoglycan hydrolases, AmiC and
These findings, together with in vitro studies of puri- EnvC, have recently been shown to localize to the septal
fied FtsZ, suggest that the rate-limiting step in turn- ring and play an important role in this process in E. coli.
over of FtsZ polymers is GTP hydrolysis. Another I will summarize some of what is known about AmiC
component of the septal ring, FtsK, is involved in and note parallels to the Atl murein hydrolase of
coordinating chromosome segregation with cell divi- Staphylococcus aureus.
sion. Recent studies have revealed that FtsK is a DNA
translocase that facilitates decatenation of sister
Cell division explained in 500 words
chromosomes by TopIV and resolution of chromo-
some dimers by the XerCD recombinase. Finally, two In E. coli, cell division is mediated by a collection of pro-
murein hydrolases, AmiC and EnvC, have been shown teins that localize to the division site, where they appear
to localize to the septal ring of Escherichia coli, where to assemble into a multiprotein complex called the septal
they play an important role in separation of daughter ring (Fig. 1) (for recent reviews, see Rothfield et al., 1999;
cells. Margolin, 2000; Errington et al., 2003; Ryan and Shapiro,
2003). The process starts with polymerization of the
tubulin-like protein FtsZ into the Z ring. The Z ring is the
Scope of this review
heart of the division apparatus – it serves as a landing
This MicroReview opens with a whirlwind tour of cell divi- pad for recruitment of other proteins to the division site,
sion in Escherichia coli. To keep it short and to the point, and might also use energy from GTP hydrolysis to drive
I have made some oversimplifications and relied almost cytokinesis. The other proteins that comprise the septal
exclusively on citations to a collection of review articles ring fall into several functional classes: (i) modulating the
rather than the original studies. The remainder of the assembly state of FtsZ (FtsA, ZipA, ZapA), (ii) connecting
review is devoted to a more detailed and critical look at a the Z ring to the cytoplasmic membrane (FtsA, ZipA), (iii)
few questions that have been the focus of several recent coordinating septation with chromosome segregation
studies. (i) How do the proteins that comprise the septal (FtsK), (iv) synthesis of peptidoglycan cell wall (FtsI,
ring work together during cytokinesis? One step towards FtsW) and (v) hydrolysis of peptidoglycan to separate
daughter cells (AmiC, EnvC). The septal ring also contains
Accepted 21 June, 2004. *For correspondence. E-mail david- many proteins of essentially unknown function [FtsEX,
weiss@uiowa.edu; Tel. (+1) 319 335 7785; Fax (+1) 319 335 9006. FtsQ, FtsL, FtsB (formerly called YgbQ) and FtsN].

© 2004 Blackwell Publishing Ltd


Fig. 1. The septal ring. Top: GFP-FtsL visualized by deconvolution
microscopy (modified from Ghigo et al., 1999). Bottom: model for
assembly of proteins into the septal ring of E. coli. First, FtsZ forms
the Z ring. FtsA and ZipA join next, independently of one another.
Once both FtsA and ZipA have localized, the remaining proteins join
the ring in the order indicated. Localization of ZapA has not been
studied in detail, and the position of EnvC (not shown) is not yet
known. Dependence of FtsK and other downstream proteins on
FtsEX is leaky (Schmidt et al., 2004).
Cell division proceeds by the concerted inward growth
of all three layers of the cell envelope – the cytoplasmic
membrane, peptidoglycan wall and outer membrane. A
plausible model for this process, first put forward by Hale
and de Boer (1997), can be updated as follows. Constric-
tion of the Z ring pulls the cytoplasmic membrane inward.
Proteins involved in peptidoglycan synthesis, such as FtsI
and FtsW, reside in the cytoplasmic membrane, so when
the membrane invaginates, peptidoglycan synthesis fol-
lows. Even as the peptidoglycan layer grows inward,
hydrolases like AmiC are at work splitting the septal
murein to separate daughter cells. Finally, the peptidogly-
can layer is connected to the outer membrane by a variety
of bridging proteins such as Lpp (Braun’s lipoprotein).
Thus, the outer membrane is expected to follow the pep-
tidoglycan passively as new bridging proteins are incor-
porated in the wake of the peptidoglycan synthases.
Spatial and temporal regulation of cell division is
accomplished primarily at the level of Z ring assembly. Two
mechanisms are particularly important: inhibition of Z ring
assembly at the midcell by nucleoid occlusion and inhibi-
tion of Z ring assembly at the poles by the Min proteins.
Nucleoid occlusion refers to the observation that Z ring
assembly is inhibited in the vicinity of the nucleoid, for
reasons that are obscure. The MinC and MinD proteins
form a complex, MinCD, which binds to FtsZ and prevents
Z ring formation. In E. coli, MinCD has the astonishing
property of oscillating from pole to pole with a period of
© 2004 Blackwell Publishing Ltd, Molecular Microbiology, 54, 588–597
The septal ring 589
ª30 s, a process that requires a third protein, MinE. Oscil-
lation involves redistribution of the Min proteins among
coiled polymers that extend along the inner surface of the
cytoplasmic membrane (Shih et al., 2003). In a variation
on this theme, MinCD of B. subtilis remains statically
associated with the poles; this requires a protein called
DivIVA that is not homologous to MinE of E. coli. The net
effect of MinCD oscillation in E. coli and polar sequestra-
tion in B. subtilis is a time-averaged concentration mini-
mum at the midcell (Meinhardt and de Boer, 2001; Howard
et al., 2001; Howard, 2004). Thus, nucleoid occlusion and
the Min system work together to ensure that the only
permissive site for Z ring assembly is the DNA-free region
that opens up at the midcell as chromosomes begin to
segregate to incipient daughter cells.
Assembly of the septal ring: a model for
protein–protein interactions?
Identifying and characterizing interactions among the pro-
teins that constitute the septal ring is important, as this
information should help us to understand how these pro-
teins work together during cytokinesis. Studies of protein
localization in various E. coli mutant backgrounds have
revealed a set of dependencies that imply the various
division proteins localize to the septal ring in a defined
order (Fig. 1) (Buddelmeijer and Beckwith, 2002; Err-
ington et al., 2003). The process starts with polymeriza-
tion of FtsZ into a contractile ring structure at the inner
face of the cytoplasmic membrane. FtsA and ZipA bind
directly to FtsZ, and localize next, presumably as the Z
ring is assembling. Z rings can assemble in mutants that
lack FtsA or ZipA, but Z rings are not observed in the
absence of both proteins (Pichoff and Lutkenhaus, 2002).
The ZapA protein, recently discovered in B. subtilis, also
binds directly to FtsZ, so one would expect it to localize
as the Z ring is assembling, but this has not been studied
yet. Once both FtsA and ZipA are in place, the remaining
proteins are recruited in the following order: [FtsE + FtsX]
(probably an ABC transporter complex) Æ FtsK Æ FtsQ
Æ [FtsL + FtsB] (probably a heterodimer) Æ FtsW Æ FtsI
Æ FtsN Æ AmiC. This order of recruitment is generally
interpreted to reflect the assembly pathway for a multipro-
tein complex, and thus makes predictions about which
proteins interact.
Several septal ring components have been shown to
bind directly to FtsZ, including ZipA, FtsA and ZapA (Hale
and de Boer, 1997; Wang et al., 1997; Gueiros-Filho and
Losick, 2002). Immunoprecipation has been used to show
that FtsE and FtsX form a complex, as predicted for an
ABC transporter (De Leeuw et al., 1999). Immunoprecip-
itation has also been used to recover a protein complex
containing FtsQ, FtsL and FtsB (Buddelmeijer and Beck-
with, 2004).
590 D. S. Weiss
Several negative regulators of Z ring assembly have
been shown to interact with FtsZ directly, including SulA,
MinC and EzrA (Hu et al., 1999; Cordell et al., 2003; Hae-
usser et al., 2004). SulA and MinC are not part of the
septal ring, but the distritubtion for EzrA is more complex.
EzrA is a negative regulator of Z ring assembly found
throughout the low-GC Gram-positive bacteria. In non-
dividing B. subtilis cells, EzA is distributed around the
cytoplasmic membrane, where it helps prevent Z rings
from assembling at inappropriate sites such as the poles.
But in dividing cells a significant fraction of the EzrA pool
is recruited to the septal ring in an FtsZ-dependent man-
ner (Levin et al., 1999).
Despite some recent progress towards identifying inter-
actions among the division proteins, it is remarkable that
so many of the expected interactions have yet to be
observed. To some extent this situation may reflect tech-
nical challenges and a lack of effort, but several observa-
tions suggest that interactions among the division proteins
may be more complex than implied by the linear order of
recruitment observed in E. coli. (i) The FtsQ–FtsL–FtsB
complex mentioned above was detected even in cells
depleted of FtsK (Buddelmeijer and Beckwith, 2004),
which is required for localization of FtsQ and downstream
proteins to the septal ring. Apparently FtsQ, FtsL and FtsB
are recruited to the septal ring as a preformed complex,
despite the fact that FtsQ can localize to the septal ring
without FtsL or FtsB. (ii) Overproduction of several pro-
teins, including FtsI and FtsQ, by ª 50-fold does not inter-
fere with division, even though much of the ‘extra’ protein
is found delocalized around the membrane or mislocalized
to the poles (Guzman et al., 1997; Weiss et al., 1999;
Boyd et al., 2000). This observation is difficult to reconcile
with high-affinity pair-wise interactions, because that
should result in sequestration of downstream division pro-
teins. Rather, it seems likely that some division proteins
only interact strongly in the context of the septal ring,
perhaps because each protein binds weakly to two or
more proteins. (iii) Most of the septal ring proteins are
associated with the cytoplasmic membrane. Colocaliza-
tion of proteins to the membrane increases their local
concentration and might allow weak protein–protein inter-
actions to drive assembly of the septal ring. However,
such weak interactions might be difficult to detect in assay
systems where the proteins are not tethered in close
proximity. (iv) The septal ring is a transient structure. It
disassembles by the end of constriction, and at least some
of its components undergo constant turnover even when
the ring is present (see below). The cooperativity that
results from a network of interactions would seem well
suited for providing both high affinity and facile disassem-
bly. (v) Most of the same division proteins exist in B.
subtilis, but exhibit considerable interdependence, as if
assembly of the septal ring is a highly concerted process
© 2004 Blackwell Publishing Ltd, Molecular Microbiology, 54, 588–597
in that organism (reviewed in Errington et al., 2003). (vi)
It is not yet known whether the proteins in the current
model represent a complete set. Six new proteins (FtsB,
ZapA, AmiC, FtsE, FtsX and EnvC) have been added to
the picture just within the last 3 years (Buddelmeijer et al.,
2002; Gueiros-Filho and Losick, 2002; Bernhardt and de
Boer, 2003; Schmidt et al., 2004; Bernhardt and de Boer,
2004).
The assertion that most interactions among the late
proteins have yet to be demonstrated needs to be quali-
fied, as there is a recent report of numerous interactions
– some expected, some not – using a bacterial two-hybrid
system based on reconstitution of a phage repressor in
E. coli (Di Lallo et al. 2003). One concern regarding the
interpretation of these experiments is that fusions were
made to full-length division proteins. Thus, the assay
might be detecting co-assembly of proteins into the septal
ring rather than simple pair-wise interactions. This caveat
aside, reconstitution of phage repressor function could
reflect direct interactions and implies at the very least that
the respective division proteins are in very close proximity,
which is more than could be inferred from observations of
colocalization by fluorescence microscopy.
Structure and function of FtsZ
Of the dozen or so proteins that comprise the septal ring,
the most highly conserved is FtsZ. Homologues of FtsZ
exist in almost all bacteria, many archaea, some chloro-
plasts and a few primitive mitochondria (Vaughan et al.,
2004). FtsZ is a prokaryotic homologue of tubulin, one of
several major cytoskeletal proteins in eukaryotic organ-
isms. Like tubulin, purified FtsZ exhibits GTPase activity
and undergoes reversible, GTP-dependent polymerization
into filaments. In vivo, FtsZ forms a contractile ring at the
division site (Bi and Lutkenhaus, 1991). As division pro-
ceeds, the Z ring constricts, so as to remain at the leading
edge of the developing septum.
FtsZ of E. coli appears to comprise four domains
(Vaughan et al., 2004). There is a short and poorly con-
served N-terminal leader (ª15 residues), a highly con-
served domain (ª300 residues) that is structurally and
functionally homologous to tubulin, a poorly conserved
linker (ª50 residues) and a well-conserved C-terminal tail
(ª15 residues). The C-terminal tail is the binding site for
two division proteins, FtsA and ZipA (Din et al., 1998; Ma
and Margolin, 1999; Hale et al., 2000; Yan et al., 2000;
Haney et al., 2001). As noted above under Assembly of
the septal ring, FtsA and ZipA are in turn required for
recruitment of downstream division proteins. Recently, a
mutant form of FtsA that can support division in the
absence of ZipA has been described (Geissler et al.,
2003). The existence of this bypass mutant may simplify
efforts to study septal ring assembly and function in vitro

and might also explain why most bacteria lack a clear ZipA
homologue.
The three-dimensional structures of FtsZ from Metha-
nococcus jannaschii and the ab-tubulin heterodimer from
beef brain were reported simultaneously, and offered
important insights into how these proteins function (for
reviews, see Nogales et al., 1998; van den Ent et al.,
2001; Romberg and Levin, 2003). Although FtsZ and
tubulin have <20% amino acid identity, they adopt very
similar folds, especially in the vicinity of the GTP binding
site, where not only the fold but also several critical amino
acid residues are highly conserved. GTP binds at one end
of the FtsZ monomer, designated the ‘plus’ end by con-
vention. Addition of another monomer completes the
GTPase catalytic site; it is the minus end of the second
monomer that interacts with GTP and the preceding sub-
unit. This binding geometry can be used to rationalize why
GTP promotes polymerization of FtsZ and why hydrolysis
of GTP is associated with depolymerization. Moreover, the
fact that amino acids involved in GTP hydrolysis are
derived from both subunits explains why FtsZ assembly is
necessary for GTP hydrolysis. Interestingly, the minus end
of FtsZ is bound by the division inhibitor SulA, which
prevents FtsZ polymerization by blocking FtsZ–FtsZ inter-
action (Cordell et al., 2003).
The FtsZ polymer in the Z ring has yet to be observed
in electron micrographs. There are several potential rea-
sons for this – it may be too small, the bacterial cytoplasm
may be too dense to provide contrast, and/or the Z ring
might not have a repetitive and ordered structure that
would make it visually distinctive. In the absence of a
telltale micrograph, conjecture as to the structure of the
FtsZ polymer in the Z ring has been guided by studies of
FtsZ polymers formed in vitro (Romberg and Levin, 2003).
Purified FtsZ assembles in a GTP-dependent fashion into
protofilaments, linear arrays of FtsZ molecules stacked
end to end. Protofilaments formed of GTP-bound FtsZ are
straight, whereas those of GDP-bound FtsZ are curved
(Lu et al., 2000). Because FtsZ protofilaments are
observed under a variety of conditions, and because sim-
ilar protofilaments are formed by tubulin, there is wide
agreement that protofilaments are the fundamental build-
ing block of the Z ring. About one-third of the cellular FtsZ
pool is present in the Z ring, making it six to eight protofil-
aments wide in some E. coli strains (Stricker et al., 2002).
How the protofilaments are arranged is very much an
open question. Because the lateral surfaces of FtsZ are
different from those of tubulin, FtsZ is unlikely to form
structures similar to microtubules (Nogales et al., 1998).
Nevertheless, protofilaments associate laterally into a
variety of higher-order structures in vitro, including pairs
of protofilaments that form tight spirals, sheets of parallel
and anti-parallel protofilaments, and bundles of protofila-
ments that are arranged in complex ways. Formation of
© 2004 Blackwell Publishing Ltd, Molecular Microbiology, 54, 588–597
The septal ring 591
these higher-order structures is promoted by cations like
Ca2+, Mg2+ and DEAE-dextran. Interestingly, two division
proteins, ZipA and ZapA, have been observed to promote
bundling in vitro, fuelling speculation that they do so in
vivo as well (RayChaudhuri, 1999; Hale et al., 2000;
Gueiros-Filho and Losick, 2002). Thus, FtsZ bundles
might be stabilized by lateral FtsZ–FtsZ interactions, by
cross-linking proteins, or a combination of the two. With
so many higher-order structures to choose from, it is dif-
ficult to say which, if any, is physiologically relevant. The
recent report of a mutant form of FtsZ that fails to support
division and can assemble in vitro into protofilaments but
not Ca2+-induced bundles strongly suggests that a higher-
order FtsZ structure is involved in cell division (Koppelman
et al., 2004).
There has been some controversy as to whether
protofilaments assembled in vitro consist primarily of
FtsZ-GTP or FtsZ-GDP (Mingorance et al., 2001; Schef-
fers and Driessen, 2002). A recent study has concluded
that FtsZ-GTP predominates (Romberg and Mitchison,
2004). Assuming that this result holds up to further anal-
ysis, why might it be interesting? As noted by Romberg
and Levin (2003), a polymer composed of FtsZ-GTP is
stable, whereas a hypothetical FtsZ-GDP polymer is likely
to be metastable – recall that this is the form that favours
depolymerization. In other words, an FtsZ-GDP polymer
would be like a loaded spring that could disassemble
rapidly, releasing the energy from many GTP hydrolysis
events all at once. But if protofilaments consist primarily
of FtsZ-GTP, they would presumably release energy in
small quanta and are not well suited for generating large
forces. This is different from microtubules, which are a
metastable assemblage of tubulin-GDP with a tubulin-
GTP ‘cap’ at the plus end. Perhaps microtubules need to
generate larger forces because they operate on a greater
geometric scale than does the Z ring.
Because the studies of what nucleotide is bound to
FtsZ in protofilaments have been carried out with purified
FtsZ in vitro, it must be noted that FtsZ polymers in vivo
could behave differently. In particular, they might consist
of FtsZ-GDP if the protofilaments engage in lateral inter-
actions that stabilize FtsZ-GDP assemblies, as is the
case for tubulin-GDP in microtubules. Alternatively, Z
ring-associated proteins might change the relative rates
of the various steps in the GTPase cycle. Despite these
caveats, studies of FtsZ dynamics in vivo support the
notion that GTP hydrolysis is the rate-limiting step in the
cycle of FtsZ assembly and disassembly in the Z ring
(see below).
Several mechanisms have been suggested for how
FtsZ might use GTP hydrolysis to power constriction of
the Z ring during septum assembly (reviewed in Ryan and
Shapiro, 2003). These are: (i) depolymerization, (ii) sliding
of stable FtsZ filaments against each other by a hypothet-
592 D. S. Weiss
ical motor protein functioning as a ratchet and (iii) curva-
ture of the polymer upon hydrolysis of GTP. While each of
these models is reasonable, it is worth noting that it has
yet to be established whether, let alone how, FtsZ powers
cytokinesis. It is widely assumed that the septal ring must
constrict against turgor pressure, which exerts an outward
force of approximately three atmospheres on the cytoplas-
mic membrane of E. coli (Cayley et al. 2000). However,
cell division is accomplished by synthesis of new cell
envelope material, so it is not clear to what extent turgor
pressure resists invagination of the cell envelope. Another
reason for suspecting that FtsZ provides energy for con-
striction is the analogy to eukaryotic cytoskeletal elements
such as actomyosin and microtubules that have been
shown unambiguously to do work in animal cells. But
while the eukaryotic proteins are perhaps best known for
their capacity to generate force, this is not their only use
(Desai and Mitchison, 1997). Microtubules, for instance,
take advantage of GTP hydrolysis-driven cycles of poly-
merization and depolymerization to probe the cytosol as
they attempt to capture chromosomes during the early
stages of mitosis. By analogy, the ultimate purpose of
GTP hydrolysis by FtsZ might be to allow facile assembly
and disassembly rather than exert force on the cell enve-
lope. Of course, these functions of GTP hydrolysis are not
mutually exclusive.
A related issue is whether energy might indeed be
needed for constriction, but something other than FtsZ is
the source. The only alternative that has received signifi-
cant attention is the idea that inward synthesis of the
peptidoglycan cell wall might ‘push’ cytokinesis. At
present, this seems unlikely because invagination of the
cytoplasmic membrane has been observed to continue in
E. coli and B. subtilis even after synthesis of septal pep-
tidoglycan has been blocked (Daniel et al., 2000; Heidrich
et al., 2002). Moreover, some bacteria lack a cell wall, but
use a Z ring for cell division (Wang and Lutkenhaus,
1996).
For the Z ring to exert force on the cell envelope, it
needs a solid connection to the cytoplasmic membrane.
There appear to be redundant mechanisms for this. ZipA
is an integral membrane protein and binds directly to
FtsZ (Hale and de Boer, 1997), but is only found in a
subset of the proteobacteria and even there the require-
ment for ZipA can be bypassed by a mutation in ftsA
(Geissler et al., 2003). FtsA also binds directly to FtsZ.
Although FtsA is nominally a soluble protein, some of it
fractionates with cytoplasmic membrane in E. coli, sug-
gesting that FtsA is a peripheral membrane protein
(Sanchez et al., 1994). Finally, Koppelman et al. (2004)
recently demonstrated that FtsZ can bind to inverted
vesicles derived from E. coli cells, indicating that FtsZ
itself has affinity for the membrane or a protein(s) in the
membrane.
© 2004 Blackwell Publishing Ltd, Molecular Microbiology, 54, 588–597
The Z ring undergoes rapid turnover
The Z ring is like a duck in the water – calm above the
surface, paddling like mad underneath. The ‘calm surface’
is a cycle of assembly, persistence, constriction, and dis-
assembly that was revealed by numerous studies using
FtsZ-GFP or immunofluorescence microscopy (e.g. Add-
inall et al., 1996; Sun and Margolin, 1998). Interestingly,
such studies also revealed that Z rings assemble as much
as 20 min before they constrict when growth is slow (dou-
bling time 85 min) (Den Blaauwen et al., 1999). The sig-
nificant lag between Z ring formation and constriction
probably reflects the time needed to complete assembly
of the septal ring, but also suggests that assembly and
constriction are regulated separately. If so, it will be impor-
tant to identify the signal that initiates constriction.
Several studies indicated that the Z ring can assemble
and disassemble rapidly, within 1 min or less (Addinall
et al., 1997; Sun and Margolin, 1998; Rueda et al., 2003).
Nevertheless, it came as a surprise when fluorescence
recovery after photobleaching (FRAP) revealed that FtsZ
molecules in the ring turn over rapidly (Fig. 2) (Stricker
et al., 2002). Briefly, a laser was used to bleach Z rings in
cells that expressed ftsZ-gfp, and return of fluorescence
to the ring, owing to exchange with unbleached FtsZ-GFP
from the cytoplasmic pool, was monitored by time-lapse
photography. The initial study found that the half-time for
remodelling in E. coli was 30 s, but more recent work,
under different experimental conditions, indicates a half-
time of about 9 s in both E. coli and B. subtilis (Anderson
et al., 2004). Because all of the other division proteins
require FtsZ for septal localization, if FtsZ subunits are
turning over, the remaining proteins in the septal ring
might be too. This expectation was confirmed for ZipA
(Stricker et al., 2002).
A number of additional interesting observations have
come from these studies. First, the rate-limiting step in
turnover is probably GTP hydrolysis. In support of this
inference, the FtsZ84(Ts) mutant protein, which has a
lesion in the GTP binding site and diminished GTPase
activity, exchanges about threefold slower than wild-type
FtsZ (Anderson et al., 2004). Moreover, the half-time of
ª 9 s for turnover of wild-type FtsZ as determined by
FRAP means that, on average, each FtsZ molecule cycles
into and out of the Z ring approximately five times per
minute. This rate is strikingly similar to the rate of GTP
hydrolysis – 5–10 GTP per FtsZ per minute – determined
in vitro under conditions that support formation of protofil-
aments (Lu et al., 1998; Romberg and Mitchison, 2004).
If the rate-limiting step in FtsZ turnover is in fact GTP
hydrolysis, the Z ring consists primarily of FtsZ-GTP and
has a limited capacity to generate force. A second intrigu-
ing finding is that turnover does not appear to be coupled
in any simple way to constriction. The rate of remodelling

Fig. 2. Rapid remodelling of the Z ring as revealed by FRAP. Live B.
subtilis cells expressing ftsZ-gfp were immobilized on a 1% agarose
pad. A laser was used to bleach half of the Z ring in one cell (large
arrow), and recovery of fluorescence was monitored by time-lapse
photography. The smaller arrowheads mark the ends of the cell, as
determined from a DIC image (B. subtilis grows as a chain of cells
under these conditions.) The recovery half-time calculated from this
series was 9.5 s. Figure courtesy of D. Anderson and H. Erickson.
is the same before and during constriction, and ftsZ84(Ts)
mutants divide fairly normally at the permissive tempera-
ture despite the diminished GTPase activity and slower
turnover of the FtsZ84 protein. These observations cau-
tion against using the observed rapid turnover of FtsZ as
support for the notion that depolymerization drives cytok-
inesis. A third remarkable finding is that elimination of
ZapA, EzrA or MinCD, all of which are implicated in mod-
ulating FtsZ assembly in vivo, had little or no effect on the
rate of Z ring remodelling (Anderson et al., 2004). Finally,
as noted by Romberg and Levin (2003), rapid turnover
has implications for the regulation of cell division. Because
the Z ring must be actively maintained, assembly of a Z
ring does not commit the cell to division at that site.
Instead, it is easy for cells to disassemble an existing
septal ring to abort division, as occurs during the SOS
response to DNA damage in E. coli (Bi and Lutkenhaus,
1993), or to redeploy FtsZ to another site, as occurs
during the switch from medial to polar septation during
sporulation in B. subtilis. (Ben-Yehuda and Losick, 2002)
© 2004 Blackwell Publishing Ltd, Molecular Microbiology, 54, 588–597
The septal ring 593
Coordinating septum assembly with
nucleoid segregation
As already mentioned, nucleoid occlusion is one mecha-
nism for linking cell division to chromosome segregation.
Another mechanism involves FtsK.
FtsK of E. coli is an enormous protein, 1329 amino
acids in length, and has several activities. The N-terminal
domain (ª200 residues) alone is sufficient to support cell
division (Draper et al., 1998; Wang and Lutkenhaus,
1998). It contains four transmembrane helices (Dorazi and
Dewar, 2000) and localizes to the septal ring, where it is
needed for recruitment of several additional essential divi-
sion proteins (Wang and Lutkenhaus, 1998; Yu et al.,
1998a; Chen and Beckwith, 2001). The essential activity
supplied by the N-terminal domain of FtsK is not entirely
clear. Its role in recruitment of downstream division pro-
teins implies an essential function in assembly of the
septal ring before the onset of cytokinesis, but there is
also evidence that the N-terminal domain of FtsK plays
additional roles during septum closure (see below).
The remainder of FtsK is cytoplasmic. It consists of a
proline- and glutamine-rich region (ª500 residues) that
might serve as a linker followed by a C-terminal domain
(ª500 residues) involved in DNA segregation (Yu et al.,
1998b; Steiner et al., 1999). The C-terminal domain
belongs to the AAA family of ATPases, a set of proteins
associated with a wide variety of cellular activities (Vale,
2000). Some AAA domains catalyse the folding and
unfolding of proteins, whereas others disassemble protein
complexes or generate unidirectional movement along
tracks.
To understand how FtsK facilitates chromosome segre-
gation, it is helpful to know that newly replicated chromo-
somes are linked, and that these linkages must be
resolved for partitioning to go to completion. One way in
which chromosomes are linked is that they are catenated.
Catenanes are resolved by Topo IV. The C-terminal
domain of FtsK interacts directly with Topo IV, recruits it
to the midcell and stimulates its decatenase activity
(Espeli et al., 2003). The other form of linkage is that
chromosomes are sometimes dimeric. Chromosome
dimers arise from recA-dependent (homologous) recom-
bination between sister chromosomes, and are resolved
by XerCD, a recombinase that acts at a 28 bp chromo-
somal site near the terminus named dif. The C-terminal
domain of FtsK activates the XerCD recombinase and
positions the dif sites so that they can form an appropriate
synapse (Aussel et al., 2002; Capiaux et al., 2002).
Finally, the cytosolic portion of FtsK is an ATP-dependent
DNA translocase (Aussel et al., 2002). There are several
possibilities, none of which are mutually exclusive, for how
the translocase activity might facilitate chromosome seg-
regation. These include aligning dif sites, creating a
594 D. S. Weiss
domain of supercoiled DNA where Topo IV acts and
pumping DNA away from the closing septum.
Depending on the growth conditions, the C-terminal
domain of FtsK is only essential in the ª 10% of cells in a
population that contain chromosome catenanes or dimers
that need to be resolved. Most of the cells in a culture
(ª 90%) divide well even if the C-terminal domain of FtsK
is absent.
FtsK belongs to a large family of proteins implicated in
DNA translocation. Another well-studied member of this
family is SpoIIIE, a protein required for sporulation in B.
subtilis. Sporulation involves an asymmetric division event
to create a large mother cell (that ultimately lyses) and a
small forespore (that ultimately matures into a spore). The
fact that cell division occurs close to one pole means that
DNA has to move farther to be properly partitioned to the
forespore than to a daughter cell during vegetative growth,
when division occurs at the midcell. For this reason,
sporulation provides an excellent model system for study-
ing chromosome movement. SpoIIIE localizes to the polar
septum, where it appears to function as a unidirectional
pump that exports DNA from the mother cell to the
nascent forespore (Bath et al., 2000; Sharp and Pogliano,
2002). In addition, the N-terminal membrane anchor
domain of SpoIIIE is needed for a membrane fusion event
at the completion of engulfment, a phagocytosis-like pro-
cess in which the cytoplasmic membrane of the mother
cell envelops the forespore (Sharp and Pogliano, 2003).
Whether FtsK participates in membrane fusion during
cell division in E. coli is not yet known. While an ftsK
depletion strain forms smooth filaments, indicating that
FtsK is required to initiate cytokinesis, several point and
truncation mutants form deep constrictions, as if these
forms of FtsK are specifically defective in the final stages
of septum closure (Begg et al., 1995; Diez et al., 1997;
Wang and Lutkenhaus, 1998; Yu et al., 1998a). These
observations are consistent with a defect in membrane
fusion, but it has also been suggested that FtsK is needed
for the final stages of peptidoglycan synthesis because
FtsK deletions can be rescued by deleting dacA, which
encodes a carboxypeptidase (Draper et al., 1998). FtsK
deletions can also be suppressed by overexpression of
FtsN (Draper et al., 1998), the structure of which has
revealed a potential peptidoglycan binding site (Yang
et al., 2004).
Separating daughter cells
The murein hydrolases, some of which function as autol-
ysins, constitute a diverse set of enzymes that attack
different types of bonds in the peptidoglycan sacculus –
lytic transglycosylases hydrolyse the glycan backbone,
amidases cleave between the glycan backbone and the
peptide side-chain, and D,D-endopeptidases cleave the
© 2004 Blackwell Publishing Ltd, Molecular Microbiology, 54, 588–597
peptide cross-links. It has long been appreciated that
murein hydrolases are needed for splitting of the septum
to separate daughter cells, but proving this point in E. coli
has been difficult because hydrolase mutants usually
grow and divide normally. This presumably results from
the tremendous redundancy of these enzymes, as there
are 18 known peptidoglycan hydrolases in E. coli. The
recent construction of mutants deleted for multiple hydro-
lase genes (up to seven) has provided the missing proof
(Heidrich et al., 2002). Septum cleavage is retarded in
such mutants, resulting in the formation of chains of cells
anywhere from 3 to 100 cells long, depending on the
number and identity of the hydrolases inactivated.
Whereas most of the known E. coli murein hydrolases
contribute to septum cleavage, two amidases, AmiA and
AmiC, appear to be especially important (Heidrich et al.,
2001). AmiA and AmiC are exported to the periplasm by
the twin-arginine protein transport (Tat) pathway, which
probably explains why Tat mutants form chains of cells
(Bernhardt and de Boer, 2003; Ize et al., 2003). An AmiA-
GFP fusion protein is distributed fairly uniformly through-
out the periplasm, but AmiC-GFP localizes to the septal
ring during cell division (Bernhardt and de Boer, 2003).
AmiC has four functional domains: an N-terminal Tat sig-
nal sequence (ª 30 residues), a targeting domain (ª 150
residues), a potential linker sequence (ª 60 residues) and
an amidase catalytic domain (ª 170 residues). Although
the Tat signal sequence is required for export, the target-
ing domain is both necessary and sufficient for localization
of GFP to the septal ring (Bernhardt and de Boer, 2003).
Localization of AmiC depends on FtsN, making AmiC the
last known recruit to the septal ring. More recently, a
second murein hydrolase that localizes to the septal ring
in E. coli has been discovered (Bernhardt and de Boer,
2004). This enzyme, named EnvC, has homology to lyso-
staphin and is probably a metal-dependent endopepti-
dase that cleaves peptide cross-links.
Some Gram-positive bacteria contain only a few murein
hydrolases, and in such organisms loss of a single hydro-
lase has been found to prevent cell separation. Of partic-
ular interest here, because of the analogy to AmiC, is the
Atl (autolysin) enzyme of S. aureus. The Atl protein local-
izes to the division site, a structure called the equatorial
surface ring, and mutants that lack atl grow as large clus-
ters of cocci (Baba and Schneewind, 1998). Localization
to the equatorial surface ring is mediated by the repeat
domains R1 to R3, which are not homologous to the
targeting domain in AmiC. The actual targets recognized
by Atl and AmiC – perhaps a protein, perhaps a modifi-
cation of the peptidoglycan – have yet to be identified.
Some issues for the future
This MicroReview has touched upon some recent insights

into the mechanism of bacterial cell division, especially
the astonishingly rapid turnover of the Z ring, the function
of FtsK and the identification of proteins responsible for
separating daughter cells once septation is complete.
Despite this progress, we still know very little about how
a mother cell becomes two daughters. Considering only
the subset of topics covered here, a number of important
questions remain to answered. Does FtsZ drive constric-
tion, and if so, how? Why is the N-terminal domain of FtsK
essential? How do the division proteins interact, and how
do these interactions enable these proteins to work
together during cytokinesis? Beyond these questions lie
many others pertaining to issues that this MicroReview
has not attempted to discuss in any serious fashion. How
is septal peptidoglycan synthesized, and how is this pro-
cess regulated? Many division proteins are of essentially
unknown function – what do they do?
Finally, given that cell division has so far only been
studied intensively in E. coli and B. subtilis, one wonders
how widely the paradigm will pertain. While genome
sequencing has revealed that the cell division proteins
known from E. coli and B. subtilis are, to a first approxi-
mation, widely conserved among the bacteria, there are
important differences (Rothfield et al., 1999; Margolin,
2000). The apparent lack of FtsZ in chlamydiae and myco-
plasma, and the recent characterization of a cyanobacte-
rial division protein with no clear homologue in E. coli or
B. subtilis (Mazouni et al., 2004), are but two examples.
At first the diversity will complicate our picture of cell
division, but ultimately themes will emerge, and with these
themes will come an understanding of which details are
just details and which are of more fundamental
importance.
Acknowledgements
I thank Laura Romberg and Ken Marians for helpful discus-
sions, Piet de Boer, Harold Erickson, Joe Lutkenhaus, Laura
Romberg and several anonymous reviewers for comments
on the manuscript. Thomas Bernhardt, Piet de Boer, David
Anderson and Harold Erickson graciously communicated
results before publication. I thank Mark Wissel for help with
preparing Fig. 1, and David Anderson and Harold Erickson
for supplying Fig. 2. The work in my lab is supported by a
grant from the National Institutes of Health (GM59893).
References
Addinall, S.G., Bi, E., and Lutkenhaus, J. (1996) FtsZ ring
formation in fts mutants. J Bacteriol 178: 3877–3884.
Addinall, S.G., Cao, C., and Lutkenhaus, J. (1997) Temper-
ature shift experiments with an ftsZ84 (Ts) strain reveal
rapid dynamics of FtsZ localization and indicate that the Z
ring is required throughout septation and cannot reoccupy
division sites once constriction has initiated. J Bacteriol
179: 4277–4284.
© 2004 Blackwell Publishing Ltd, Molecular Microbiology, 54, 588–597
The septal ring 595
Anderson, D.E., Gueiros-Filho, F.J., and Erickson, H.P.
(2004) Assembly dynamics of FtsZ rings in Bacillus subtilis
and Escherichia coli, the effects of FtsZ-regulating pro-
teins. J Bacteriol 186: 5775–5781.
Aussel, L., Barre, F.X., Aroyo, M., Stasiak, A., Stasiak, A.Z.,
and Sherratt, D. (2002) FtsK is a DNA motor protein that
activates chromosome dimer resolution by switching the
catalytic state of the XerC and XerD recombinases. Cell
108: 195–205.
Baba, T., and Schneewind, O. (1998) Targeting of muralytic
enzymes to the cell division site of Gram-positive bacteria:
repeat domains direct autolysin to the equatorial surface
ring of Staphylococcus aureus. EMBO J 17: 4639–4646.
Bath, J., Wu, L.J., Errington, J., and Wang, J.C. (2000) Role
of Bacillus subtilis SpoIIIE in DNA transport across the
mother cell-prespore division septum. Science 290: 995–
997.
Begg, K.J., Dewar, S.J., and Donachie, W.D. (1995) A new
Escherichia coli cell division gene, ftsK. J Bacteriol 177:
6211–6222.
Ben-Yehuda, S., and Losick, R. (2002) Asymmetric cell divi-
sion in B. subtilis involves a spiral-like intermediate of the
cytokinetic protein FtsZ. Cell 109: 257–266.
Bernhardt, T.G., and de Boer, P.A. (2003) The Escherichia
coli amidase AmiC is a periplasmic septal ring component
exported via the twin-arginine transport pathway. Mol
Microbiol 48: 1171–1182.
Bernhardt, T.G., and de Boer, P.A. (2004) Screening for
synthetic lethal mutants in Escherichia coli and identifica-
tion of EnvC (YibP) as a periplasmic septal ring factor with
murein hydrolase activity. Mol Microbiol 52: 1255–1269.
Bi, E., and Lutkenhaus, J. (1993) Cell division inhibitors SulA
and MinCD prevent formation of the FtsZ ring. J Bacteriol
175: 1118–1125.
Bi, E.F., and Lutkenhaus, J. (1991) FtsZ ring structure asso-
ciated with division in Escherichia coli. Nature 354: 161–
164.
Boyd, D., Weiss, D.S., Chen, J.C., and Beckwith, J. (2000)
Towards single-copy gene expression systems making
gene cloning physiologically relevant: lambda InCh, a sim-
ple Escherichia coli plasmid-chromosome shuttle system.
J Bacteriol 182: 842–847.
Buddelmeijer, N., and Beckwith, J. (2002) Assembly of cell
division proteins at the E. coli cell center. Curr Opin Micro-
biol 5: 553–557.
Buddelmeijer, N., and Beckwith, J. (2004) A complex of the
Escherichia coli division proteins FtsL, FtsB and FtsQ
forms independently of its localization to the septal region.
Mol Microbiol 52: 1315–1327.
Buddelmeijer, N., Judson, N., Boyd, D., Mekalanos, J.J., and
Beckwith, J. (2002) YgbQ, a cell division protein in Escher-
ichia coli and Vibrio cholerae, localizes in codependent
fashion with FtsL to the division site. Proc Natl Acad Sci
USA 99: 6316–6321.
Capiaux, H., Lesterlin, C., Perals, K., Louarn, J.M., and
Cornet, F. (2002) A dual role for the FtsK protein in Escher-
ichia coli chromosome segregation. EMBO Rep 3: 532–
536.
Cayley, D.S., Guttman, H.J., and Record, M.T., Jr (2000)
Biophysical characterization of changes in amounts and
activity of Escherichia coli cell and compartment water and
596 D. S. Weiss
turgor pressure in response to osmotic stress. Biophys J
78: 1748–1764.
Chen, J.C., and Beckwith, J. (2001) FtsQ, FtsL and FtsI
require FtsK, but not FtsN, for co-localization with FtsZ
during Escherichia coli cell division. Mol Microbiol 42: 395–
413.
Cordell, S.C., Robinson, E.J., and Lowe, J. (2003) Crystal
structure of the SOS cell division inhibitor SulA and in
complex with FtsZ. Proc Natl Acad Sci USA 100: 7889–
7894.
Daniel, R.A., Harry, E.J., and Errington, J. (2000) Role of
penicillin-binding protein PBP 2B in assembly and function-
ing of the division machinery of Bacillus subtilis. Mol Micro-
biol 35: 299–311.
De Leeuw, E., Graham, B., Phillips, G.J., ten Hagen-Jong-
man, C.M., Oudega, B., and Luirink, J. (1999) Molecular
characterization of Escherichia coli FtsE and FtsX. Mol
Microbiol 31: 983–993.
Den Blaauwen, T., Buddelmeijer, N., Aarsman, M.E.,
Hameete, C.M., and Nanninga, N. (1999) Timing of FtsZ
assembly in Escherichia coli. J Bacteriol 181: 5167–5175.
Desai, A., and Mitchison, T.J. (1997) Microtubule polymer-
ization dynamics. Annu Rev Cell Dev Biol 13: 83–117.
Di Lallo, G., Fagioli, M., Barionovi, D., Ghelardini, P., and
Paolozzi, L. (2003) Use of a two-hybrid assay to study the
assembly of a complex multicomponent protein machinery:
bacterial septosome differentiation. Microbiology 149:
3353–3359.
Diez, A.A., Farewell, A., Nannmark, U., and Nystrom, T.
(1997) A mutation in the ftsK gene of Escherichia coli
affects cell–cell separation, stationary-phase survival,
stress adaptation, and expression of the gene encoding
the stress protein UspA. J Bacteriol 179: 5878–5883.
Din, N., Quardokus, E.M., Sackett, M.J., and Brun, Y.V.
(1998) Dominant C-terminal deletions of FtsZ that affect its
ability to localize in Caulobacter and its interaction with
FtsA. Mol Microbiol 27: 1051–1063.
Dorazi, R., and Dewar, S.J. (2000) Membrane topology of the
N-terminus of the Escherichia coli FtsK division protein.
FEBS Lett 478: 13–18.
Draper, G.C., McLennan, N., Begg, K., Masters, M., and
Donachie, W.D. (1998) Only the N-terminal domain of FtsK
functions in cell division. J Bacteriol 180: 4621–4627.
van den Ent, F., Amos, L., and Lowe, J. (2001) Bacterial
ancestry of actin and tubulin. Curr Opin Microbiol 4: 634–
638.
Errington, J., Daniel, R.A., and Scheffers, D.J. (2003) Cytok-
inesis in bacteria. Microbiol Mol Biol Rev 67: 52–65.
Espeli, O., Lee, C., and Marians, K.J. (2003) A physical and
functional interaction between Escherichia coli FtsK and
topoisomerase IV. J Biol Chem 278: 44639–44644.
Geissler, B., Elraheb, D., and Margolin, W. (2003) A gain-of-
function mutation in ftsA bypasses the requirement for the
essential cell division gene zipA in Escherichia coli. Proc
Natl Acad Sci USA 100: 4197–4202.
Ghigo, J.-M., Weiss, D.S., Chen, J.C., Yarrow, J.C., and
Beckwith, J. (1999) Localization of FtsL to the Escherichia
coli septal ring. Mol Microbiol 31: 725–737.
Gueiros-Filho, F.J., and Losick, R. (2002) A widely conserved
bacterial cell division protein that promotes assembly of the
tubulin-like protein FtsZ. Genes Dev 16: 2544–2556.
© 2004 Blackwell Publishing Ltd, Molecular Microbiology, 54, 588–597
Guzman, L.M., Weiss, D.S., and Beckwith, J. (1997) Domain-
swapping analysis of FtsI, FtsL, and FtsQ, bitopic mem-
brane proteins essential for cell division in Escherichia coli.
J Bacteriol 179: 5094–5103.
Haeusser, D.P., Schwartz, R.L., Smith, A.M., Oates, M.E.,
and Levin, P.A. (2004) EzrA prevents aberrant cell division
by modulating assembly of the cytoskeletal protein FtsZ.
Mol Microbiol 52: 801–814.
Hale, C.A., and de Boer, P.A. (1997) Direct binding of FtsZ
to ZipA, an essential component of the septal ring structure
that mediates cell division in E. coli. Cell 88: 175–185.
Hale, C.A., Rhee, A.C., and de Boer, P.A. (2000) ZipA-
induced bundling of FtsZ polymers mediated by an inter-
action between C-terminal domains. J Bacteriol 182:
5153–5166.
Haney, S.A., Glasfeld, E., Hale, C., Keeney, D., He, Z., and
de Boer, P. (2001) Genetic analysis of the Escherichia coli
FtsZ.ZipA interaction in the yeast two-hybrid system. Char-
acterization of FtsZ residues essential for the interactions
with ZipA and with FtsA. J Biol Chem 276: 11980–11987.
Heidrich, C., Templin, M.F., Ursinus, A., Merdanovic, M.,
Berger, J., Schwarz, H., et al. (2001) Involvement of N-
acetylmuramyl-L-alanine amidases in cell separation and
antibiotic-induced autolysis of Escherichia coli. Mol Micro-
biol 41: 167–178.
Heidrich, C., Ursinus, A., Berger, J., Schwarz, H., and Holtje,
J.V. (2002) Effects of multiple deletions of murein hydro-
lases on viability, septum cleavage, and sensitivity to large
toxic molecules in Escherichia coli. J Bacteriol 184: 6093–
6099.
Howard, M. (2004) A mechanism for polar protein localization
in bacteria. J Mol Biol 335: 655–663.
Howard, M., Rutenberg, A.D., and de Vet, S. (2001) Dynamic
compartmentalization of bacteria: accurate division in E.
Coli. Phys Rev Lett 87: 278102.
Hu, Z., Mukherjee, A., Pichoff, S., and Lutkenhaus, J. (1999)
The MinC component of the division site selection system
in Escherichia coli interacts with FtsZ to prevent polymer-
ization. Proc Natl Acad Sci USA 96: 14819–14824.
Ize, B., Stanley, N.R., Buchanan, G., and Palmer, T. (2003)
Role of the Escherichia coli Tat pathway in outer membrane
integrity. Mol Microbiol 48: 1183–1193.
Koppelman, C.M., Aarsman, M.E., Postmus, J., Pas, E.,
Muijsers, A.O., Scheffers, D.J., et al. (2004) R174 of
Escherichia coli FtsZ is involved in membrane interaction
and protofilament bundling, and is essential for cell divi-
sion. Mol Microbiol 51: 645–657.
Levin, P.A., Kurtser, I.G., and Grossman, A.D. (1999) Iden-
tification and characterization of a negative regulator of
FtsZ ring formation in Bacillus subtilis. Proc Natl Acad Sci
USA 96: 9642–9647.
Lu, C., Reedy, M., and Erickson, H.P. (2000) Straight and
curved conformations of FtsZ are regulated by GTP hydrol-
ysis. J Bacteriol 182: 164–170.
Lu, C., Stricker, J., and Erickson, H.P. (1998) FtsZ from
Escherichia coli, Azotobacter vinelandii, and Thermotoga
maritima – quantitation, GTP hydrolysis, and assembly.
Cell Motil Cytoskeleton 40: 71–86.
Ma, X., and Margolin, W. (1999) Genetic and functional anal-
yses of the conserved C-terminal core domain of Escher-
ichia coli FtsZ. J Bacteriol 181: 7531–7544.

Margolin, W. (2000) Themes and variations in prokaryotic cell
division. FEMS Microbiol Rev 24: 531–548.
Mazouni, K., Domain, F., Cassier-Chauvat, C., and Chauvat,
F. (2004) Molecular analysis of the key cytokinetic compo-
nents of cyanobacteria: FtsN, ZipN and MinCDE. Mol
Microbiol 52: 1145–1158.
Meinhardt, H., and de Boer, P.A. (2001) Pattern formation in
Escherichia coli: a model for the pole-to-pole oscillations
of Min proteins and the localization of the division site. Proc
Natl Acad Sci USA 98: 14202–14207.
Mingorance, J., Rueda, S., Gomez-Puertas, P., Valencia, A.,
and Vicente, M. (2001) Escherichia coli FtsZ polymers
contain mostly GTP and have a high nucleotide turnover.
Mol Microbiol 41: 83–91.
Nogales, E., Downing, K.H., Amos, L.A., and Lowe, J. (1998)
Tubulin and FtsZ form a distinct family of GTPases. Nat
Struct Biol 5: 451–458.
Pichoff, S., and Lutkenhaus, J. (2002) Unique and overlap-
ping roles for ZipA and FtsA in septal ring assembly in
Escherichia coli. EMBO J 21: 685–693.
RayChaudhuri, D. (1999) ZipA is a MAP-Tau homolog and
is essential for structural integrity of the cytokinetic FtsZ
ring during bacterial cell division. EMBO J 18: 2372–
2383.
Romberg, L., and Levin, P.A. (2003) Assembly dynamics of
the bacterial cell division protein FTSZ: poised at the edge
of stability. Annu Rev Microbiol 57: 125–154.
Romberg, L., and Mitchison, T.J. (2004) Rate-limiting gua-
nosine 5¢-triphosphate hydrolysis during nucleotide turn-
over by FtsZ, a prokaryotic tubulin homologue involved in
bacterial cell division. Biochemistry 43: 282–288.
Rothfield, L., Justice, S., and Garcia-Lara, J. (1999) Bacterial
cell division. Annu Rev Genet 33: 423–448.
Rueda, S., Vicente, M., and Mingorance, J. (2003) Concen-
tration and assembly of the division ring proteins FtsZ,
FtsA, and ZipA during the Escherichia coli cell cycle. J
Bacteriol 185: 3344–3351.
Ryan, K.R., and Shapiro, L. (2003) Temporal and spatial
regulation in prokaryotic cell cycle progression and devel-
opment. Annu Rev Biochem 72: 367–394.
Sanchez, M., Valencia, A., Ferrandiz, M.J., Sander, C., and
Vicente, M. (1994) Correlation between the structure and
biochemical activities of FtsA, an essential cell division
protein of the actin family. EMBO J 13: 4919–4925.
Scheffers, D.J., and Driessen, A.J. (2002) Immediate GTP
hydrolysis upon FtsZ polymerization. Mol Microbiol 43:
1517–1521.
Schmidt, K.L., Peterson, N.D., Kustusch, R.J., Wissel, M.C.,
Graham, B., Phillips, G.J., and Weiss, D.S. (2004) A pre-
dicted ABC transporter, FtsEX, is needed for cell division
in Escherichia coli. J Bacteriol 186: 785–793.
Sharp, M.D., and Pogliano, K. (2002) Role of cell-specific
SpoIIIE assembly in polarity of DNA transfer. Science 295:
137–139.
© 2004 Blackwell Publishing Ltd, Molecular Microbiology, 54, 588–597
The septal ring 597
Sharp, M.D., and Pogliano, K. (2003) The membrane domain
of SpoIIIE is required for membrane fusion during Bacillus
subtilis sporulation. J Bacteriol 185: 2005–2008.
Shih, Y.L., Le, T., and Rothfield, L. (2003) Division site selec-
tion in Escherichia coli involves dynamic redistribution of
Min proteins within coiled structures that extend between
the two cell poles. Proc Natl Acad Sci USA 100: 7865–
7870.
Steiner, W., Liu, G., Donachie, W.D., and Kuempel, P. (1999)
The cytoplasmic domain of FtsK protein is required for
resolution of chromosome dimers. Mol Microbiol 31: 579–
583.
Stricker, J., Maddox, P., Salmon, E.D., and Erickson, H.P.
(2002) Rapid assembly dynamics of the Escherichia coli
FtsZ-ring demonstrated by fluorescence recovery after
photobleaching. Proc Natl Acad Sci USA 99: 3171–3175.
Sun, Q., and Margolin, W. (1998) FtsZ dynamics during the
division cycle of live Escherichia coli cells. J Bacteriol 180:
2050–2056.
Vale, R.D. (2000) AAA proteins. Lords of the ring. J Cell Biol
150: F13–F19.
Vaughan, S., Wickstead, B., Gull, K., and Addinall, S.G.
(2004) Molecular evolution of FtsZ protein sequences
encoded within the genomes of archaea, bacteria, and
eukaryota. J Mol Evol 58: 19–29.
Wang, X., Huang, J., Mukherjee, A., Cao, C., and Lutken-
haus, J. (1997) Analysis of the interaction of FtsZ with
itself, GTP, and FtsA. J Bacteriol 179: 5551–5559.
Wang, X., and Lutkenhaus, J. (1996) Characterization of the
ftsZ gene from Mycoplasma pulmonis, an organism lacking
a cell wall. J Bacteriol 178: 2314–2319.
Wang, L., and Lutkenhaus, J. (1998) FtsK is an essential
cell division protein that is localized to the septum and
induced as part of the SOS response. Mol Microbiol 29:
731–740.
Weiss, D.S., Chen, J.C., Ghigo, J.M., Boyd, D., and Beckwith,
J. (1999) Localization of FtsI (PBP3) to the septal ring
requires its membrane anchor, the Z ring, FtsA, FtsQ, and
FtsL. J Bacteriol 181: 508–520.
Yan, K., Pearce, K.H., and Payne, D.J. (2000) A conserved
residue at the extreme C-terminus of FtsZ is critical for the
FtsA–FtsZ interaction in Staphylococcus aureus. Biochem
Biophys Res Commun 270: 387–392.
Yang, J.C., Van Den Ent, F., Neuhaus, D., Brevier, J., and
Lowe, J. (2004) Solution structure and domain architec-
ture of the divisome protein FtsN. Mol Microbiol 52: 651–
660.
Yu, X.C., Tran, A.H., Sun, Q., and Margolin, W. (1998a)
Localization of cell division protein FtsK to the Escherichia
coli septum and identification of a potential N-terminal tar-
geting domain. J Bacteriol 180: 1296–1304.
Yu, X.C., Weihe, E.K., and Margolin, W. (1998b) Role of the
C terminus of FtsK in Escherichia coli chromosome segre-
gation. J Bacteriol 180: 6424–6428.