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43-600: 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 ( F ilamenting t emperature s ensitive). 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

86-410: 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

129-400: A discussion of Translocation factors and the role of GTP, see signal recognition particle (SRP). While tubulin and related structural proteins also bind and hydrolyze GTP as part of their function to form intracellular tubules, these proteins utilize a distinct tubulin domain that is unrelated to the G domain used by signaling GTPases. There are also GTP-hydrolyzing proteins that use

172-518: A fellow of the American Academy of Microbiology . Lutkenhaus discovered, among other things, that the FtsZ protein forms a ring around the division plane in bacteria and is thus a key factor in bacterial cell division. This article about an American educator is a stub . You can help Misplaced Pages by expanding it . GTPase GTPases are a large family of hydrolase enzymes that bind to

215-476: 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

258-493: 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

301-532: Is a professor at the University of Kansas Medical Center . He received a B.S. in organic chemistry from Iowa state University and then a PhD in biochemistry for the University of California, Los Angeles. Following his PhD, Lutkenhaus pursued his postdoctoral studies with William Donachie at the University of Edinburgh and then continued at the University of Connecticut Health Science center. In 2002, Lutkenhaus became

344-598: 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. 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

387-401: 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

430-619: Is defined by loss of two beta-strands and additional N-terminal strands. Both namesakes of this superfamily, myosin and kinesin , have shifted to use ATP. See dynamin as a prototype for large monomeric GTPases. Much of the SIMIBI class of GTPases is activated by dimerization. Named after the signal recognition particle (SRP), MinD, and BioD, the class is involved in protein localization, chromosome partitioning, and membrane transport. Several members of this class, including MinD and Get3, has shifted in substrate specificity to become ATPases. For

473-416: 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. FtsZ polymerization

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516-913: 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

559-468: Is named after the prototypical member, the translation factor G proteins. They play roles in translation, signal transduction, and cell motility. Multiple classical translation factor family GTPases play important roles in initiation , elongation and termination of protein biosynthesis . Sharing a similar mode of ribosome binding due to the β-EI domain following the GTPase, the most well-known members of

602-572: Is returned to being GDP bound, the two parts of the heterotrimer re-associate to the original, inactive state. The heterotrimeric G proteins can be classified by sequence homology of the α unit and by their functional targets into four families: G s family, G i family, G q family and G 12 family. Each of these G α protein families contains multiple members, such that the mammals have 16 distinct α -subunit genes. The G β and G γ are likewise composed of many members, increasing heterotrimer structural and functional diversity. Among

645-461: Is terminated by hydrolysis of bound GTP to bound GDP. This can occur through the intrinsic GTPase activity of the α subunit, or be accelerated by separate regulatory proteins that act as GTPase-activating proteins (GAPs), such as members of the Regulator of G protein signaling (RGS) family). The speed of the hydrolysis reaction works as an internal clock limiting the length of the signal. Once G α

688-402: 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

731-439: 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 protein domain common to many GTPases. GTPases function as molecular switches or timers in many fundamental cellular processes. Examples of these roles include: GTPases are active when bound to GTP and inactive when bound to GDP. In

774-485: 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

817-550: The G protein complex and to promote binding of GTP in its place. The GTP-bound complex undergoes an activating conformation shift that dissociates it from the receptor and also breaks the complex into its component G protein alpha and beta-gamma subunit components. While these activated G protein subunits are now free to activate their effectors, the active receptor is likewise free to activate additional G proteins – this allows catalytic activation and amplification where one receptor may activate many G proteins. G protein signaling

860-486: The GTP binding/GTPase domain flanked by long regulatory regions, while the beta and gamma subunits form a stable dimeric complex referred to as the beta-gamma complex . When activated, a heterotrimeric G protein dissociates into activated, GTP-bound alpha subunit and separate beta-gamma subunit, each of which can perform distinct signaling roles. The α and γ subunit are modified by lipid anchors to increase their association with

903-564: 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

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946-481: The ability to polymerize into filaments. FtsZ has the ability to 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 hydrolyzing activity of

989-483: The active lifetime of signaling GTPases. Some GTPases have little to no intrinsic GTPase activity, and are entirely dependent on GAP proteins for deactivation (such as the ADP-ribosylation factor or ARF family of small GTP-binding proteins that are involved in vesicle-mediated transport within cells). To become activated, GTPases must bind to GTP. Since mechanisms to convert bound GDP directly into GTP are unknown,

1032-482: 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

1075-518: 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 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. Joe Lutkenhaus Joe Lutkenhaus

1118-608: The family are EF-1A / EF-Tu , EF-2 / EF-G , and class 2 release factors . Other members include EF-4 (LepA), BipA (TypA), SelB (bacterial selenocysteinyl-tRNA EF-Tu paralog), Tet ( tetracycline resistance by ribosomal protection), and HBS1L (eukaryotic ribosome rescue protein similar to release factors). The superfamily also includes the Bms1 family from yeast. Heterotrimeric G protein complexes are composed of three distinct protein subunits named alpha (α), beta (β) and gamma (γ) subunits . The alpha subunits contain

1161-838: The first-identified such protein, named Ras , they are also referred to as Ras superfamily GTPases. Small GTPases generally serve as molecular switches and signal transducers for a wide variety of cellular signaling events, often involving membranes, vesicles or cytoskeleton. According to their primary amino acid sequences and biochemical properties, the many Ras superfamily small GTPases are further divided into five subfamilies with distinct functions: Ras , Rho ("Ras-homology"), Rab , Arf and Ran . While many small GTPases are activated by their GEFs in response to intracellular signals emanating from cell surface receptors (particularly growth factor receptors ), regulatory GEFs for many other small GTPases are activated in response to intrinsic cell signals, not cell surface (external) signals. This class

1204-412: The function of these effectors. Hydrolysis of GTP bound to an (active) G domain-GTPase leads to deactivation of the signaling/timer function of the enzyme. The hydrolysis of the third (γ) phosphate of GTP to create guanosine diphosphate (GDP) and P i , inorganic phosphate , occurs by the S N 2 mechanism (see nucleophilic substitution ) via a pentacoordinate transition state and is dependent on

1247-461: The generalized receptor-transducer-effector signaling model of Martin Rodbell , signaling GTPases act as transducers to regulate the activity of effector proteins. This inactive-active switch is due to conformational changes in the protein distinguishing these two forms, particularly of the "switch" regions that in the active state are able to make protein-protein contacts with partner proteins that alter

1290-399: The inactive GTPases are induced to release bound GDP by the action of distinct regulatory proteins called guanine nucleotide exchange factors or GEFs. The nucleotide-free GTPase protein quickly rebinds GTP, which is in far excess in healthy cells over GDP, allowing the GTPase to enter the active conformation state and promote its effects on the cell. For many GTPases, activation of GEFs is

1333-483: The inactive, GDP-bound state. The amount of active GTPase can be changed in several ways: In most GTPases, the specificity for the base guanine versus other nucleotides is imparted by the base-recognition motif, which has the consensus sequence [N/T]KXD. The following classification is based on shared features; some examples have mutations in the base-recognition motif that shift their substrate specificity, most commonly to ATP. The TRAFAC class of G domain proteins

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1376-495: The inner leaflet of the plasma membrane. Heterotrimeric G proteins act as the transducers of G protein-coupled receptors , coupling receptor activation to downstream signaling effectors and second messengers . In unstimulated cells, heterotrimeric G proteins are assembled as the GDP bound, inactive trimer (G α -GDP-G βγ complex). Upon receptor activation, the activated receptor intracellular domain acts as GEF to release GDP from

1419-416: 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. The number of multidrug-resistant bacterial strains is currently increasing; thus, the determination of drug targets for

1462-399: 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

1505-438: 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

1548-552: The presence of a magnesium ion Mg . GTPase activity serves as the shutoff mechanism for the signaling roles of GTPases by returning the active, GTP-bound protein to the inactive, GDP-bound state. Most "GTPases" have functional GTPase activity, allowing them to remain active (that is, bound to GTP) only for a short time before deactivating themselves by converting bound GTP to bound GDP. However, many GTPases also use accessory proteins named GTPase-activating proteins or GAPs to accelerate their GTPase activity. This further limits

1591-592: The primary control mechanism in the stimulation of the GTPase signaling functions, although GAPs also play an important role. For heterotrimeric G proteins and many small GTP-binding proteins, GEF activity is stimulated by cell surface receptors in response to signals outside the cell (for heterotrimeric G proteins, the G protein-coupled receptors are themselves GEFs, while for receptor-activated small GTPases their GEFs are distinct from cell surface receptors). Some GTPases also bind to accessory proteins called guanine nucleotide dissociation inhibitors or GDIs that stabilize

1634-424: 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

1677-559: 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. The formation of the Z-ring closely coincides with cellular processes associated with replication. Z-ring formation coincides with

1720-439: 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

1763-518: The target molecules of the specific G proteins are the second messenger-generating enzymes adenylyl cyclase and phospholipase C , as well as various ion channels . Small GTPases function as monomers and have a molecular weight of about 21 kilodaltons that consists primarily of the GTPase domain. They are also called small or monomeric guanine nucleotide-binding regulatory proteins, small or monomeric GTP-binding proteins, or small or monomeric G-proteins, and because they have significant homology with

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1806-409: 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

1849-469: 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 , FtsZ1 and FtsZ2 . During cell division , FtsZ

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