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FtsZ is a
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
encoded by the ''ftsZ''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
that assembles into a ring at the future site of
bacterial Bacteria (; singular: bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among ...
cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
(also called the Z ring). FtsZ is a
prokaryotic A prokaryote () is a Unicellular organism, single-celled organism that lacks a cell nucleus, nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek language, Greek wikt:πρό#Ancient Greek, πρό (, 'before') a ...
homologue of the
eukaryotic Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
protein
tubulin Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...
. The initials FtsZ mean "Filamenting temperature-sensitive mutant Z." The hypothesis was that cell division mutants of ''
E. coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' would grow as filaments due to the inability of the daughter cells to separate from one another. FtsZ is found in almost all bacteria, many archaea, all chloroplasts and some mitochondria, where it is essential for cell division. FtsZ assembles the cytoskeletal scaffold of the Z ring that, along with additional proteins, constricts to divide the cell in two.


History

In the 1960s scientists screened for temperature sensitive mutations that blocked cell division at 42 °C. The mutant cells divided normally at 30°, but failed to divide at 42°. Continued growth without division produced long filamentous cells (Filamenting temperature sensitive). Several such mutants were discovered and mapped to a locus originally named ''ftsA,'' which could be one or more genes''.'' In 1980 Lutkenhaus and Donachie showed that several of these mutations mapped to one gene, ''ftsA,'' but one well-characterized mutant, PAT84, originally discovered by Hirota et al, mapped to a separate, adjacent gene. They named this cell division gene ''ftsZ.'' In 1991 Bi and Lutkenhaus used immunogold electron microscopy to show that FtsZ localized to the invaginating septum at midcell. Subsequently, the Losick and Margolin groups used immuno-fluorescence microscopy and GFP fusions to show that FtsZ assembled Z rings early in the cell cycle, well before the septum began to constrict. Other division proteins then assemble onto the Z ring and constriction occurs in the last part of the cell cycle. In 1992-3 three labs independently discovered that FtsZ was related to eukaryotic tubulin, which is the protein subunit that assembles into microtubules. This was the first discovery that bacteria have homologs of eukaryotic cytoskeletal proteins. Later work showed that FtsZ was present in, and essential for, cell division in almost all bacteria and in many but not all archaea. Mitochondria and chloroplasts are eukaryotic organelles that originated as bacterial endosymbionts, so there was much interest in whether they use FtsZ for division. Chloroplast FtsZ was first discovered by Osteryoung, and it is now known that all chloroplasts use FtsZ for division. Mitochondrial FtsZ was discovered by Beech in an alga; FtsZ is used for mitochondrial division in some eukaryotes, while others have replaced it with a dynamin-based machinery. In 2014, scientists identified two FtsZ homologs in
archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...
, FtsZ1 and
FtsZ2 FtsZ is a protein encoded by the ''ftsZ'' gene that assembles into a ring at the future site of bacterial cell division (also called the Z ring). FtsZ is a prokaryotic homologue of the eukaryotic protein tubulin. The initials FtsZ mean "Filamen ...
.


Function

During
cell division Cell division is the process by which a parent cell (biology), cell divides into two daughter cells. Cell division usually occurs as part of a larger cell cycle in which the cell grows and replicates its chromosome(s) before dividing. In eukar ...
, FtsZ is the first protein to move to the division site, and is essential for recruiting other proteins that produce a new
cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mech ...
(
septum In biology, a septum (Latin for ''something that encloses''; plural septa) is a wall, dividing a cavity or structure into smaller ones. A cavity or structure divided in this way may be referred to as septate. Examples Human anatomy * Interatri ...
) between the dividing cells. FtsZ's role in cell division is analogous to that of actin in eukaryotic cell division, but, unlike the
actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...
-
myosin Myosins () are a superfamily of motor proteins best known for their roles in muscle contraction and in a wide range of other motility processes in eukaryotes. They are ATP-dependent and responsible for actin-based motility. The first myosin ...
ring in eukaryotes, FtsZ has no known
motor protein Motor proteins are a class of molecular motors that can move along the cytoplasm of cells. They convert chemical energy into mechanical work by the hydrolysis of ATP. Flagellar rotation, however, is powered by a proton pump. Cellular functions ...
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
chloroplast A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it in ...
s and some
mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
further establishes their prokaryotic ancestry.
L-form bacteria L-form bacteria, also known as L-phase bacteria, L-phase variants or cell wall-deficient (CWD) bacteria, are growth forms derived from different bacteria. They lack cell walls. Peptidoglycan (murein) is absent. Two types of L-forms are distinguish ...
that lack a
cell wall A cell wall is a structural layer surrounding some types of cells, just outside the cell membrane. It can be tough, flexible, and sometimes rigid. It provides the cell with both structural support and protection, and also acts as a filtering mech ...
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 Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...
and
microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 11 an ...
, but little is known about these activities in FtsZ. While it is known that single-stranded
tubulin Tubulin in molecular biology can refer either to the tubulin protein superfamily of globular proteins, or one of the member proteins of that superfamily. α- and β-tubulins polymerize into microtubules, a major component of the eukaryotic cytoske ...
protofilaments form into 13 stranded
microtubules Microtubules are polymers of tubulin that form part of the cytoskeleton and provide structure and shape to eukaryotic cells. Microtubules can be as long as 50 micrometres, as wide as 23 to 27  nm and have an inner diameter between 11 an ...
, 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 In molecular biology, treadmilling is a phenomenon observed within protein filaments of the cytoskeletons of many cells, especially in actin filaments and microtubules. It occurs when one end of a filament grows in length while the other end shri ...
(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
segrosome Segrosomes are protein complexes that ensure accurate segregation (partitioning) of plasmids or chromosomes during bacterial cell division. Just as higher forms of life have evolved a complex mitotic apparatus to partition duplicated DNA during ...
s, 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")

FtsZ has the ability to bind to GTP and also exhibits a
GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
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 hydrolyzing 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 as to 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 FtsA is a bacterial protein that is related to actin by overall structural similarity and in its ATP binding pocket. Along with other bacterial actin homologs such as MreB, ParM, and MamK, these proteins suggest that eukaryotic actin has a co ...
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 FtsA is a bacterial protein that is related to actin by overall structural similarity and in its ATP binding pocket. Along with other bacterial actin homologs such as MreB, ParM, and MamK, these proteins suggest that eukaryotic actin has a co ...
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 ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'', 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 ''Bacillus subtilis'', known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium, found in soil and the gastrointestinal tract of ruminants, humans and marine sponges. As a member of the genus ''Bacillus' ...
''. 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 ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'', 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 ''Bacillus subtilis'', known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium, found in soil and the gastrointestinal tract of ruminants, humans and marine sponges. As a member of the genus ''Bacillu ...
'' and ''
Caulobacter crescentus ''Caulobacter crescentus'' is a Gram-negative, oligotrophic bacterium widely distributed in fresh water lakes and streams. The taxon is more properly known as ''Caulobacter vibrioides'' (Henrici and Johnson 1935). ''C. crescentus'' is an importa ...
''. However, other species including ''
Streptococcus pneumoniae ''Streptococcus pneumoniae'', or pneumococcus, is a Gram-positive, spherical bacteria, alpha-hemolytic (under aerobic conditions) or beta-hemolytic (under anaerobic conditions), aerotolerant anaerobic member of the genus Streptococcus. They are ...
'' and ''
Myxococcus xanthus ''Myxococcus xanthus'' is a gram-negative, rod-shaped species of myxobacteria that exhibits various forms of self-organizing behavior in response to environmental cues. Under normal conditions with abundant food, it exists as a predatory, saproph ...
'' 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 repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA da ...
. 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 knockout A gene knockout (abbreviation: KO) is a genetic technique in which one of an organism's genes is made inoperative ("knocked out" of the organism). However, KO can also refer to the gene that is knocked out or the organism that carries the gene kno ...
s result in cells that divide without respect to the
nucleoid The nucleoid (meaning ''nucleus-like'') is an irregularly shaped region within the prokaryotic cell that contains all or most of the genetic material. The chromosome of a prokaryote is circular, and its length is very large compared to the cell dim ...
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 In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer, monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are ...
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

The number of multidrug-resistant bacterial strains is currently increasing; thus, the determination of drug targets for the development of novel antimicrobial drugs is urgently needed. The potential role of FtsZ in the blockage of cell division, together with its high degree of
conservation Conservation is the preservation or efficient use of resources, or the conservation of various quantities under physical laws. Conservation may also refer to: Environment and natural resources * Nature conservation, the protection and manageme ...
across bacterial species, makes FtsZ a highly attractive target for developing novel antibiotics. Researchers have been working on synthetic molecules and natural products as inhibitors of FtsZ. The spontaneous self-assembly of FtsZ can also be used in nanotechnology to fabricate metal nanowires.


See also

* * *


References

{{DEFAULTSORT:Ftsz Bacterial proteins Cytoskeleton proteins