Treadmilling

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Actin Treadmilling Mechanism. This figure assumes that the critical concentration at the positive end is less than the critical concentration at the negative end and that the cytosolic subunit concentration is in between the positive and negative end critical concentrations. Actin Treadmilling Mechanism .jpg
Actin Treadmilling Mechanism. This figure assumes that the critical concentration at the positive end is less than the critical concentration at the negative end and that the cytosolic subunit concentration is in between the positive and negative end critical concentrations.

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 shrinks, resulting in a section of filament seemingly "moving" across a stratum or the cytosol. This is due to the constant removal of the protein subunits from these filaments at one end of the filament, while protein subunits are constantly added at the other end. [1] Treadmilling was discovered by Wegner, [2] who defined the thermodynamic and kinetic constraints. Wegner recognized that: “The equilibrium constant (K) for association of a monomer with a polymer is the same at both ends, since the addition of a monomer to each end leads to the same polymer.”; a simple reversible polymer can’t treadmill; ATP hydrolysis is required. GTP is hydrolyzed for microtubule treadmilling.

Contents

Detailed process

Dynamics of the filament

The cytoskeleton is a highly dynamic part of a cell and cytoskeletal filaments constantly grow and shrink through addition and removal of subunits. Directed crawling motion of cells such as macrophages relies on directed growth of actin filaments at the cell front (leading edge).

Microfilaments

The two ends of an actin filament differ in their dynamics of subunit addition and removal. They are thus referred to as the plus end (with faster dynamics, also called barbed end) and the minus end (with slower dynamics, also called pointed end). [3] This difference results from the fact that subunit addition at the minus end requires a conformational change of the subunits. [4] Note that each subunit is structurally polar and has to attach to the filament in a particular orientation. [5] As a consequence, the actin filaments are also structurally polar.

Elongating the actin filament occurs when free-actin (G-actin) bound to ATP associates with the filament. Under physiological conditions, it is easier for G-actin to associate at the positive end of the filament, and harder at the negative end. [6] However, it is possible to elongate the filament at either end. Association of G-actin into F-actin is regulated by the critical concentration outlined below. Actin polymerization can further be regulated by profilin and cofilin. [6] Cofilin functions by binding to ADP-actin on the negative end of the filament, destabilizing it, and inducing depolymerization. Profilin induces ATP binding to G-actin so that it can be incorporated onto the positive end of the filament.

Microtubules

Two main theories exist on microtubule movement within the cell: dynamic instability and treadmilling. [7] Dynamic instability occurs when the microtubule assembles and disassembles at one end only, while treadmilling occurs when one end polymerizes while the other end disassembles.

Critical concentration

The critical concentration is the concentration of either G-actin (actin) or the alpha,beta- tubulin complex (microtubules) at which the end will remain in an equilibrium state with no net growth or shrinkage. [6] What determines whether the ends grow or shrink is entirely dependent on the cytosolic concentration of available monomer subunits in the surrounding area. [8] Critical concentration differs from the plus (CC+) and the minus end (CC−), and under normal physiological conditions, the critical concentration is lower at the plus end than the minus end. Examples of how the cytosolic concentration relates to the critical concentration and polymerization are as follows:

Note that the cytosolic concentration of the monomer subunit between the CC+ and CC− ends is what is defined as treadmilling in which there is growth at the plus end, and shrinking on the minus end.

The cell attempts to maintain a subunit concentration between the dissociation constants at the plus and minus ends of the polymer.

Microtubule treadmilling

Microtubules formed from pure tubulin undergo subunit uptake and loss at ends by both random exchange diffusion, and by a directional (treadmilling) element. [9]   Treadmilling is inefficient, and for microtubules at steady state: the Wegner s-value1 (the reciprocal of the number of molecular events required for the net uptake of a subunit) is equal to 0.0005-0.001; i.e., it requires >1000 events. [10] Microtubule treadmilling with pure tubulin also occurs with growing microtubules [11] and is enhanced by proteins that bind to ends11.  Rapid treadmilling occurs in cells. [12] [13] [14]

FtsZ treadmilling

The bacterial tubulin homolog FtsZ is one of the best documented treadmilling polymers. FtsZ assembles into protofilaments that are one subunit thick, which can further associate into small patches of parallel protofilaments. Single filaments and/or patches have been demonstrated to treadmill in vitro [15] [16] and inside bacterial cells. [17] [18] A Monte Carlo model of FtsZ treadmilling has been designed, based on a conformational change of subunits upon polymerization and GTP hydrolysis. [19]

Related Research Articles

<span class="mw-page-title-main">Microtubule</span> Polymer of tubulin that forms part of the cytoskeleton

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 and 15 nm. They are formed by the polymerization of a dimer of two globular proteins, alpha and beta tubulin into protofilaments that can then associate laterally to form a hollow tube, the microtubule. The most common form of a microtubule consists of 13 protofilaments in the tubular arrangement.

<span class="mw-page-title-main">Cytoskeleton</span> Network of filamentous proteins that forms the internal framework of cells

The cytoskeleton is a complex, dynamic network of interlinking protein filaments present in the cytoplasm of all cells, including those of bacteria and archaea. In eukaryotes, it extends from the cell nucleus to the cell membrane and is composed of similar proteins in the various organisms. It is composed of three main components: microfilaments, intermediate filaments, and microtubules, and these are all capable of rapid growth and or disassembly depending on the cell's requirements.

<span class="mw-page-title-main">Microfilament</span> Filament in the cytoplasm of eukaryotic cells

Microfilaments, also called actin filaments, are protein filaments in the cytoplasm of eukaryotic cells that form part of the cytoskeleton. They are primarily composed of polymers of actin, but are modified by and interact with numerous other proteins in the cell. Microfilaments are usually about 7 nm in diameter and made up of two strands of actin. Microfilament functions include cytokinesis, amoeboid movement, cell motility, changes in cell shape, endocytosis and exocytosis, cell contractility, and mechanical stability. Microfilaments are flexible and relatively strong, resisting buckling by multi-piconewton compressive forces and filament fracture by nanonewton tensile forces. In inducing cell motility, one end of the actin filament elongates while the other end contracts, presumably by myosin II molecular motors. Additionally, they function as part of actomyosin-driven contractile molecular motors, wherein the thin filaments serve as tensile platforms for myosin's ATP-dependent pulling action in muscle contraction and pseudopod advancement. Microfilaments have a tough, flexible framework which helps the cell in movement.

<span class="mw-page-title-main">Actin</span> Family of proteins

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 100 μM; its mass is roughly 42 kDa, with a diameter of 4 to 7 nm.

<span class="mw-page-title-main">FtsZ</span> Protein encoded by the ftsZ gene

FtsZ is a protein encoded by the ftsZ gene that assembles into a ring at the future site of bacterial cell division. FtsZ is a prokaryotic homologue of the eukaryotic protein tubulin. The initials FtsZ mean "Filamenting temperature-sensitive mutant Z." The hypothesis was that cell division mutants of E. coli 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.

<span class="mw-page-title-main">Tubulin</span> Superfamily of proteins that make up microtubules

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 cytoskeleton. It was discovered and named by Hideo Mōri in 1968. Microtubules function in many essential cellular processes, including mitosis. Tubulin-binding drugs kill cancerous cells by inhibiting microtubule dynamics, which are required for DNA segregation and therefore cell division.

In cell biology, microtubule-associated proteins (MAPs) are proteins that interact with the microtubules of the cellular cytoskeleton. MAPs are integral to the stability of the cell and its internal structures and the transport of components within the cell.

<span class="mw-page-title-main">Growth cone</span> Large actin extension of a developing neurite seeking its synaptic target

A growth cone is a large actin-supported extension of a developing or regenerating neurite seeking its synaptic target. It is the growth cone that drives axon growth. Their existence was originally proposed by Spanish histologist Santiago Ramón y Cajal based upon stationary images he observed under the microscope. He first described the growth cone based on fixed cells as "a concentration of protoplasm of conical form, endowed with amoeboid movements". Growth cones are situated on the tips of neurites, either dendrites or axons, of the nerve cell. The sensory, motor, integrative, and adaptive functions of growing axons and dendrites are all contained within this specialized structure.

<span class="mw-page-title-main">ADF/Cofilin family</span> Family of actin-binding proteins

ADF/cofilin is a family of actin-binding proteins associated with the rapid depolymerization of actin microfilaments that give actin its characteristic dynamic instability. This dynamic instability is central to actin's role in muscle contraction, cell motility and transcription regulation.

Cytochalasins are fungal metabolites that have the ability to bind to actin filaments and block polymerization and the elongation of actin. As a result of the inhibition of actin polymerization, cytochalasins can change cellular morphology, inhibit cellular processes such as cell division, and even cause cells to undergo apoptosis. Cytochalasins have the ability to permeate cell membranes, prevent cellular translocation and cause cells to enucleate. Cytochalasins can also have an effect on other aspects of biological processes unrelated to actin polymerization. For example, cytochalasin A and cytochalasin B can also inhibit the transport of monosaccharides across the cell membrane, cytochalasin H has been found to regulate plant growth, cytochalasin D inhibits protein synthesis and cytochalasin E prevents angiogenesis.

<span class="mw-page-title-main">Protein filament</span> Long chain of protein monomers

In biology, a protein filament is a long chain of protein monomers, such as those found in hair, muscle, or in flagella. Protein filaments form together to make the cytoskeleton of the cell. They are often bundled together to provide support, strength, and rigidity to the cell. When the filaments are packed up together, they are able to form three different cellular parts. The three major classes of protein filaments that make up the cytoskeleton include: actin filaments, microtubules and intermediate filaments.

In cell biology, microtubule nucleation is the event that initiates de novo formation of microtubules (MTs). These filaments of the cytoskeleton typically form through polymerization of α- and β-tubulin dimers, the basic building blocks of the microtubule, which initially interact to nucleate a seed from which the filament elongates.

<span class="mw-page-title-main">Mitotic inhibitor</span> Cell division inhibitor

A mitotic inhibitor, microtubule inhibitor, or tubulin inhibitor, is a drug that inhibits mitosis, or cell division, and is used in treating cancer, gout, and nail fungus. These drugs disrupt microtubules, which are structures that pull the chromosomes apart when a cell divides. Mitotic inhibitors are used in cancer treatment, because cancer cells are able to grow through continuous division that eventually spread through the body (metastasize). Thus, cancer cells are more sensitive to inhibition of mitosis than normal cells. Mitotic inhibitors are also used in cytogenetics, where they stop cell division at a stage where chromosomes can be easily examined.

<span class="mw-page-title-main">Prokaryotic cytoskeleton</span> Structural filaments in prokaryotes

The prokaryotic cytoskeleton is the collective name for all structural filaments in prokaryotes. It was once thought that prokaryotic cells did not possess cytoskeletons, but advances in visualization technology and structure determination led to the discovery of filaments in these cells in the early 1990s. Not only have analogues for all major cytoskeletal proteins in eukaryotes been found in prokaryotes, cytoskeletal proteins with no known eukaryotic homologues have also been discovered. Cytoskeletal elements play essential roles in cell division, protection, shape determination, and polarity determination in various prokaryotes.

Catastrophin is a term use to describe proteins that are associated with the disassembly of microtubules. Catastrophins affect microtubule shortening, a process known as microtubule catastrophe.

Actin remodeling is the biochemical process that allows for the dynamic alterations of cellular organization. The remodeling of actin filaments occurs in a cyclic pattern on cell surfaces and exists as a fundamental aspect to cellular life. During the remodeling process, actin monomers polymerize in response to signaling cascades that stem from environmental cues. The cell's signaling pathways cause actin to affect intracellular organization of the cytoskeleton and often consequently, the cell membrane. Again triggered by environmental conditions, actin filaments break back down into monomers and the cycle is completed. Actin-binding proteins (ABPs) aid in the transformation of actin filaments throughout the actin remodeling process. These proteins account for the diverse structure and changes in shape of Eukaryotic cells. Despite its complexity, actin remodeling may result in complete cytoskeletal reorganization in under a minute.

<span class="mw-page-title-main">MDia1</span> Protein

mDia1 is a member of the protein family called the formins and is a Rho effector. It is the mouse version of the diaphanous homolog 1 of Drosophila. mDia1 localizes to cells' mitotic spindle and midbody, plays a role in stress fiber and filopodia formation, phagocytosis, activation of serum response factor, formation of adherens junctions, and it can act as a transcription factor. mDia1 accelerates actin nucleation and elongation by interacting with barbed ends of actin filaments. The gene encoding mDia1 is located on Chromosome 18 of Mus musculus and named Diap1.

<span class="mw-page-title-main">Cytoskeletal drugs</span> Substances or medications that interact with actin or tubulin

Cytoskeletal drugs are small molecules that interact with actin or tubulin. These drugs can act on the cytoskeletal components within a cell in three main ways. Some cytoskeletal drugs stabilize a component of the cytoskeleton, such as taxol, which stabilizes microtubules, or Phalloidin, which stabilizes actin filaments. Others, such as Cytochalasin D, bind to actin monomers and prevent them from polymerizing into filaments. Drugs such as demecolcine act by enhancing the depolymerisation of already formed microtubules. Some of these drugs have multiple effects on the cytoskeleton: for example, Latrunculin both prevents actin polymerization as well as enhancing its rate of depolymerization. Typically the microtubule targeting drugs can be found in the clinic where they are used therapeutically in the treatment of some forms of cancer. As a result of the lack of specificity for specific type of actin, the use of these drugs in animals results in unacceptable off-target effects. Despite this, the actin targeting compounds are still useful tools that can be used on a cellular level to help further our understanding of how this complex part of the cells' internal machinery operates. For example, Phalloidin that has been conjugated with a fluorescent probe can be used for visualizing the filamentous actin in fixed samples.

<span class="mw-page-title-main">FtsA</span> Bacterial protein that is related to actin

FtsA is a bacterial protein that is related to actin by overall structural similarity and in its ATP binding pocket.

<span class="mw-page-title-main">Neurotubule</span>

Neurotubules are microtubules found in neurons in nervous tissues. Along with neurofilaments and microfilaments, they form the cytoskeleton of neurons. Neurotubules are undivided hollow cylinders that are made up of tubulin protein polymers and arrays parallel to the plasma membrane in neurons. Neurotubules have an outer diameter of about 23 nm and an inner diameter, also known as the central core, of about 12 nm. The wall of a neurotubule is about 5 nm in width. There is a non-opaque clear zone surrounding the neurotubule and it is about 40 nm in diameter. Like microtubules, neurotubules are greatly dynamic and their length can be adjusted by polymerization and depolymerization of tubulin.

References

  1. ↑ Bruce Alberts, Dennis Bray, Julian Lewis: Molecular Biology of the Cell, 4th Edition, Taylor & Francis, 2002, pp. 909-920, ISBN   0-8153-4072-9
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  11. ↑ Arpag, G; Lawrence, EJ; Farmer, VJ; Hall, SL; Zanic, M (June 2020). "Collective effects of XMAP215, EB1, CLASP2, and MCAK lead to robust microtubule treadmilling". Proc Natl Acad Sci U S A. 117 (23): 66–78. Bibcode:2020PNAS..11712847A. doi: 10.1073/pnas.2003191117 . PMC   7293651 . PMID   32457163.
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  14. ↑ Rothwell, SW; Grasser, WA; Murphy, DB (Nov 1985). "Direct observation of microtubule treadmilling by electron microscopy". J Cell Biol. 101 (5 Pt 1): 1637–1642. doi:10.1083/jcb.101.5.1637. PMC   2113982 . PMID   4055889.
  15. ↑ Loose, Martin; Mitchison, Timothy J. (2013-12-08). "The bacterial cell division proteins FtsA and FtsZ self-organize into dynamic cytoskeletal patterns". Nature Cell Biology. 16 (1): 38–46. doi:10.1038/ncb2885. ISSN   1465-7392. PMC   4019675 . PMID   24316672.
  16. ↑ Ramirez-Diaz, Diego A.; García-Soriano, Daniela A.; Raso, Ana; Mücksch, Jonas; Feingold, Mario; Rivas, Germán; Schwille, Petra (2018-05-18). "Treadmilling analysis reveals new insights into dynamic FtsZ ring architecture". PLOS Biology. 16 (5): e2004845. doi: 10.1371/journal.pbio.2004845 . ISSN   1545-7885. PMC   5979038 . PMID   29775478.
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  18. ↑ Yang, X.; et, al (2017). "GTPase activity-coupled treadmilling of the bacterial tubulin FtsZ organizes septal cell wall synthesis". Science. 355 (6326): 744–747. Bibcode:2017Sci...355..744Y. doi:10.1126/science.aak9995. PMC   5851775 . PMID   28209899.
  19. ↑ Corbin, Lauren C.; Erickson, Harold P. (2020). "A Unified Model for Treadmilling and Nucleation of Single-Stranded FtsZ Protofilaments". Biophysical Journal. 119 (4): 792–805. Bibcode:2020BpJ...119..792C. doi:10.1016/j.bpj.2020.05.041. ISSN   0006-3495. PMC   7451871 . PMID   32763138.
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