of bacterial cells (top right of electron micrograph). During
cell division, FtsZ is the first protein to move to the division site, and is essential for recruiting other proteins that produce a new
cell wall (
septum) between the dividing cells. FtsZ's role in cell division is analogous to that of actin in eukaryotic cell division, but, unlike the
actin-
myosin ring in eukaryotes, FtsZ has no known
motor protein associated with it. Cell wall synthesis may externally push the cell membrane, providing the force for cytokinesis. Supporting this, in
E. coli the rate of division is affected by mutations in cell wall synthesis. Alternatively, FtsZ may pull the membrane from the inside based on Osawa (2009) showing the protein's contractile force on liposomes with no other proteins present. Erickson (2009) proposed how the roles of tubulin-like proteins and actin-like proteins in cell division became reversed in an evolutionary mystery. The use of the FtsZ ring in dividing
chloroplasts and some
mitochondria further establishes their prokaryotic ancestry.
L-form bacteria that lack a
cell wall do not require FtsZ for division, which implies that bacteria may have retained components of an ancestral mode of cell division. Much is known about the dynamic polymerization activities of
tubulin and
microtubules, but little is known about these activities in FtsZ. While it is known that single-stranded
tubulin protofilaments form into 13 stranded
microtubules, the multistranded structure of the FtsZ-containing Z-ring is not known. It is only speculated that the structure consists of overlapping protofilaments. Nevertheless, recent work with purified FtsZ on supported lipid bilayers as well as imaging FtsZ in living bacterial cells revealed that FtsZ protofilaments have polarity and move in one direction by
treadmilling (see also below). Recently, proteins similar to tubulin and FtsZ have been discovered in large plasmids found in
Bacillus species. They are believed to function as components of
segrosomes, which are multiprotein complexes that partition chromosomes/plasmids in bacteria. The plasmid homologs of tubulin/FtsZ seem to have conserved the ability to polymerize into filaments.
The contractile ring (the "Z ring") image of Z-rings (green) at different stages of constriction in two
E. coli cells. FtsZ can bind to
GTP and also exhibits a
GTPase domain that allows it to hydrolyze GTP to GDP and a phosphate group.
In vivo, FtsZ forms filaments with a repeating arrangement of subunits, all arranged head-to-tail. These filaments form a ring around the longitudinal midpoint, or septum, of the cell. This ring is called the Z-ring. The GTP hydrolysis activity of the protein is not essential to the formation of filaments or cell division. Mutants defective in GTPase activity often still divide, but sometimes form twisted and disordered septa. It is unclear whether FtsZ actually provides the physical force that results in division or serves as a scaffold for other proteins to execute division. There are two models for how FtsZ might generate a constriction force. One model is based on the observation that FtsZ protfilaments can be straight or curved. The transition from straight to curved is suggested to generate a bending force on the membrane. Another model is based on sliding protofilaments. Computer models and
in vivo measurements suggest that single FtsZ filaments cannot sustain a length more than 30 subunits long. In this model, FtsZ scission force comes from the relative lateral movement of subunits. Lines of FtsZ would line up together parallel and pull on each other creating a "cord" of many strings that tightens itself. In other models, FtsZ does not provide the contractile force but provides the cell a spatial scaffold for other proteins to execute the division of the cell. This is akin to the creating of a temporary structure by construction workers to access hard-to-reach places of a building. The temporary structure allows unfettered access and ensures that the workers can reach all places. If the temporary structure is not correctly built, the workers will not be able to reach certain places, and the building will be deficient. The scaffold theory is supported by information that shows that the formation of the ring and localization to the membrane requires the concerted action of a number of accessory proteins. ZipA or the actin homologue
FtsA permit initial FtsZ localization to the membrane. Following localization to the membrane, division proteins of the Fts family are recruited for ring assembly. Many of these proteins direct the synthesis of the new division septum at midcell (FtsI, FtsW), or regulate the activity of this synthesis (FtsQ, FtsL, FtsB, FtsN). The timing of Z-ring formation suggests the possibility of a spatial or temporal signal that permits the formation of FtsZ filaments. Recent super-resolution imaging in several species supports a dynamic scaffold model, in which small clusters of FtsZ protofilaments or protofilament bundles move unidirectionally around the ring's circumference by treadmilling, anchored to the membrane by
FtsA and other FtsZ-specific membrane tethers. The speed of treadmilling depends on the rate of GTP hydrolysis within the FtsZ protofilaments, but in
Escherichia coli, synthesis of the division septum remains the rate limiting step for cytokinesis. The treadmilling action of FtsZ is required for proper synthesis of the division septum by septal peptidoglycan synthesis enzymes, suggesting that these enzymes can track the growing ends of the filaments.
Septal localization and intracellular signaling The formation of the Z-ring closely coincides with cellular processes associated with replication. Z-ring formation coincides with the termination of genome replication in
E. coli and 70% of chromosomal replication in
B. subtilis. The timing of Z-ring formation suggests the possibility of a spatial or temporal signal that permits the formation of FtsZ filaments. In
Escherichia coli, at least two negative regulators of FtsZ assembly form a bipolar gradient, such that the concentration of active FtsZ required for FtsZ assembly is highest at mid-cell between the two segregating chromosomes, and lowest at the poles and over the chromosomes. This type of regulation seems to occur in other species such as
Bacillus subtilis and
Caulobacter crescentus. However, other species including
Streptococcus pneumoniae and
Myxococcus xanthus seem to use positive regulators that stimulate FtsZ assembly at mid-cell.
Communicating distress FtsZ polymerization is also linked to stressors like
DNA damage. DNA damage induces a variety of proteins to be manufactured, one of them called
SulA. SulA prevents the polymerization and GTPase activity of FtsZ. SulA accomplishes this task by binding to self-recognizing FtsZ sites. By sequestering FtsZ, the cell can directly link DNA damage to inhibiting cell division.
Preventing DNA damage Like SulA, there are other mechanisms that prevent cell division that would result in disrupted genetic information sent to daughter cells. So far, two proteins have been identified in
E. coli and
B. subtilis that prevent division over the nucleoid region: Noc and
SlmA. Noc
gene knockouts result in cells that divide without respect to the
nucleoid region, resulting in its asymmetrical partitioning between the daughter cells. The mechanism is not well understood, but thought to involve sequestration of FtsZ, preventing
polymerization over the nucleoid region. The mechanism used by SlmA to inhibit FtsZ polymerization over the nucleoid is better understood, and uses two separate steps. One domain of SlmA binds to a FtsZ polymer, then a separate domain of SlmA severs the polymer. A similar mechanism is thought to be used by MinC, another inhibitor of FtsZ polymerization involved in positioning of the FtsZ ring. == Clinical significance ==