Cellular Cytoskeletal System
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- Created by: amazingemilyjones
- Created on: 14-04-19 12:13
Cellular Cytoskeletal System
Cellular Cytoskeletal System
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The Cell Cytoskeleton
- A dynamic three-dimensional structure that fills the cytosol
- The cytoskeleton comprises a filamentous network that serves to maintain cell shape and to regulate and implement important dynamic cellular functions
- Function:
- Cell shape and orientation
- Organelle movement
- Cell division
- Cell migration
- Eukaryotic cells contain three main kinds of cytoskeletal filaments
- Microfilaments, microtubules and intermediate filaments
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Cytoskeletal System: Structure
Composition
- Protein polymers
- Contain thousands of identical subunits
- Allows rapid reorganisation
- Each filament type is formed by polymerisation of a distinct type of protein subunit
- Has its own characteristic shape and intracellular distribution
- Distinct size (diameter)
- Microtubule - 25nm
- Actin filament - 7nm
- Intermediate filament - 8-10nm
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Microfilaments
- Polymers of the protein actin
Actin filaments:
- Ubiquitously expressed
- Give shape to the cell surface
- Important for motility (ability to move spontaneously and actively, consuming energy in the process)
- Essential for mobility (ability of an object to be moved) and contraction of cells during cell division
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Actin Filaments
- Thinnest filament of cytoskeleton
- Fine, thread-like protein fibres, ~7nm in diameter
- Comprised of actin subunits
- Present as either a free monomer called G-actin (globular) or as part of a linear polymer microfilament called F-actin (filamentous)
- Actin is a family of globular multi-functional proteins that form microfilaments or actin filaments
- An actin protein's mass is roughly 42kDa
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Actin Filaments: Function
- Microfilament functions
- Cell shape and orientation
- Muscle contraction
- Movement of organelles
- Cell division
- Cell migration
- Actin function depends on interaction with actin binding proteins (ABPs)
- Over 150 known ABPs:
- ~25% of cellular protein
- Bind to g-actin and regulate polymerisation
- Bind to f-actin and impart structural diversity
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Acting Binding Proteins Modify Actin Function
- Bind to g-actin and regulate polymerisation
- Latrunculin (natural product/toxin producted by certain sponges) sequesters G-actin and prevents F-actin assembly
- Gelsolin (cytoplasmic, calcium-regulated) is an actin binding protein that is a key regulator of actin filament assembly and disassembly
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Cell Shape
- Microfilaments interact with each other
- ABP bind to f-actin and impart structural diversity
- The association of various actin binding proteins can affect how the actin filaments are organised
- For example they can be tightly cross linked in parallel polarised arrays to form bundles (microvilli) or loosely associated to form a meshwork (platelet)
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Actin and Cell Migration
- ABPs remodel the cellular cytoskeleton
- Impart strength
- Important for cell migration
- Cellular migration requires orchestrated movement in cells in particular directions to specific locations
- Tissue formation during embryonic development (embryogenesis)
- Wound healing
- Axon growth
- Immune responses (phagocytosis)
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Phagocytic Cells
Early infection - microbes that penetrate the skin or mucous membranes encounter phagocytic cells
- Neutrophils
- Chemo-attraction to site of infection
- Amoeboid movement
- Phagocytic
- Destroyed during response
- Monocytes
- More effective phagocytic defense
- Circulate than migrate to infected tissue
- Enlarge and become macrophages
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Phagocytic Cells
- Macrophages
- Wander or permanently reside in connective tissue or organs
- Amoeboid cells that phagocytose microbes and cell debris
- Phagocytic Cell Migration
- Phagocytic cells are attracted to damaged tissue by chemical signals (chemokines)
- Neutrophils followed by monocytes (macrophages)
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Actin and Cell Migration
- Cellular migration occurs in three stages:
- Protrusion of leading edge - rapid actin polymerisation at the cell's front edge
- Attachment of leading edge (provides traction) - actin filaments link the cell to extracellular substrates
- Contraction (movement of main cell body forward) - myosin
- Head region interacts with actin
- Tail region binds to plasma membrane
- Movement of myosin along actin filament causes membrane and cell contraction
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Actin and Cell Migration
- Protrusion - rapid growth of actin filaments needed to push membrane forward
- lamellipodia and filipodia formation
- Actin and ARPs (actin related proteins)
- Adhesion - adhesive interaction between membrane and substrate
- Actin interaction with integrins
- Contraction - generation of internal contractile force
- Supports forward movement
- Interaction of actin filaments with motor proteins (myosin)
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Actin Filament Dysfunction
- The first case of neutrophil actin dysfunction (NAD) was reported in 1974; a male infant with a severe neutrophil motility disorder and poorly polymerisable actin
- A genetic disorder
- Neutrophil Actin Dysfunction is associated with impaired phagocytic uptake
- Actin targeting drugs
- Stabilise, depolymerise, polymerise or rearrangement of F-actin filaments - responsible for changes of cellular function
- Actin targeting drugs are divided into three major classes
- Cytochalasins, latrunculins and jasplakinolides
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Microtubules
- Polymers of the proteint tubulin
- Major components of the cytoskeleton
- Function:
- Structural support
- Intracellular transport
- DNA segregation
- Tubulin protein - superfamily of globular proteins
- alpha and beta tubulins polymerise into microtubules
- Microtubules are hollow tubes ~25nm in diameter
- Comprised of tubulin dimers - alpha and beta subunits
- Tubulin dimers are organised in 13 parallel protofilaments
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Microtubules: Dynamic Instability
- They have a very dynamic behaviour, binding GTP for polymerisation
- Dynamic assembly and turnover
- Allows cell to rapidly reorganise cytoskeleton
- GTP hydrolysis plays important role
- To form microtubules, the dimers of alpha and beta tubulin bind to GTP
- GTP-dimers assemble onto the (+) ends of microtubules
- Beta tubulin is exposed on the (+) end while the alpha tubulin is exposed on the (-) end
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Microtubules - Dynamic Instability
- After incorporation of the dimer into the microtubule, GTP on betat-tubulin hydrolyses into GDP
- Whether beta-tubulin is bound to GTP or GDP influences dimer stability
- Dimers bound to GTP tend to assemble into microtubules (growing microtubule)
- Dimers bound to GDP tend to fall apart (shrinking microtubule)
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Microtubules - Formation
- Microtubule growth requires nucleation
- event that initiates de novo formation of microtubules
- Occurs at distinct structures, e.g. Centrosome
- is an organelle that serves as the main microtubule organising centre (MTOC)
- the structure from which microtubules energy
- MTOC functions:
- Regulator or cell-cycle progression
- Organisation of eukaryotic flagella and cilia
- Organisation of the mitotic and meiotic spindle apparatus - separate the chromosomes during cell division
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Microtubles - Centrosome
- Centrosome (microtubule organisating centre) - made up of centrioles (perpendicular rings; 9 triplets of tubulin)
- Centriole
- Mother centriole
- Distal ends
- Distal appendages
- Subdistal appendages
- Proximal ends
- Microtubule triplets
- Interconnecting fibres
- Microtubules
- Pericentriolar material
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Microtubles - Centrosome
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Microtubules: Function
- Provide a set of 'tracks' for organelles and vesicles
- Interaction with motor proteins
- Provide structual support
- Form the spindle fibres for separating chromosomes during mitosis
- Arranged inside cilia to enable locomotion
- Active transport of organelles within cytoplasm
- Endocytosis
- Exocytosis
- Mitochondria movement
- Protein transport between endoplasmic reticulum and Golgi appratus
- Organelle transport and cell division - requires interaction with motor proteins
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Microtubules and Motor Proteins
- Motor proteins generate force and 'walk' along microtubules
- Kinesins - move toward (+) end
- Dynesins - move toward (-) end
- 'head' domain binds microtubule
- 'tail' domain binds membrane or cargo
- Motor proteins function in concert with microtubules
- Provide transport for organelles and vesicles
- Kinesins move along microtubule filaments, and are powered by the hydrolysis of adenosine triphosphate (ATP)
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Microtubule Drugs
- Microtubules are involved in various cellular processes, cell division, cell cycle and cell proliferation
- Crucial in the development and maintenance of cell shape, in the transport of vesicles, mitochondria and other components throughout cells, in cell signalling and in cell division and mitosis
- Two classes:
- inhibit tubulin polymerisation
- promote tubulin polymerisation
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Microtubule-Disrupting Drugs
- Tubulin-binding drugs kill cancerous cells by inhibitng microtubule dynamics, which are required for DNA segregation and therefore cell division
- Agents which stabilise microtubules:
- Taxanes (e.g. Paclitaxel (Taxol))
- Ovarian and breast cancers
- Prevent dissociation of tubulin subunits
- Block mitosis (stabilise GDP-bound tubulin)
- Agents which destabilise microtubules
- Colchicine
- Inflammatory conditions (arthritis, gout) promote disassembly of microtubles - dramatic change in organelle location, blocks migration of white blood cells - reduction of inflammation
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Intermediate Filaments
- Composed of various proteins, depending on the type of cell in which they are found
- Averaging 10nm in diameter
- More stable (strongly bound) than actin filaments
- Heterogeneous component of the cytoskeleton
- Formed by heterogeneous class of proteins
- Diameter ~10nm
- Frequently found:
- anchored to plasma membrane at cell-cell junctions
- within nucleus
- Impart resistance to stress
- An intermediate filament is a strong fibre composed of intermediate filament protein subunits - not dynamic structures
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Intermediate Filament Assembly
- The central rod domains of two polypeptides wind around each other in a coiled structure to form dimers
- Dimers then associate in a staggered antiparallel fashion to form tetramers
- Tetramers associate end to end to form protofilaments and laterally to form filaments
- Each filament contains approximately eight protofilaments wound around each other in a ropelike structure
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Intermediate Filaments
- Toughest of cytoskeletal components
- Further stabilised through interaction with accessory proteins
- plectin (links cytoskeleton to plasma membrane, connects cells)
- Impart resistance to stress
- Like actin filaments, they function in the maintenance of cell shape by bearing tension (during mitosis and during the positioning of the centrosome)
- By contrast to microtubules, they resist compression
- Organise the internal 3D cell structure
- Anchoring of organelles
- Structural components of the nuclear lamina
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Intermediate Filaments
- Participate in some cell-cell connections
- in combination with proteins and desmosomes
- Anchor cell-matrix junctionsAllows the cell to communicate to adjust structures of the tissue based on signals from the cell environment
- used in messaging between cells
- Whereas actin filaments and microtubules are polymers of single types of proteins (actin and tubulin), intermediate filaments are composed of a variety of proteins that are expressed in different types of cells
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Intermediate Filaments
- Categorised into four classes:
- Type 1: keratins
- hair and nails
- Type 2: vimentin
- cellular membranes
- connective tissue and muscle
- Type 3: neurofilaments
- Type 4: nuclear lamins
- coats lumen of nucleus
- involved in dissolution of nuclear membrane in mitosis
- Type 1: keratins
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Intermediate Filaments
- Abnormalities of neurofilaments result in disease of motor neurons, particularly amyotrophic lateral sclerosis (ALS)
- ALS (Lou Gehrig's disease; motor neurone disease)
- Stephen Hawking
- Progressive loss of motor neurons
- Leads to muscle atrophy, paralysis and eventual death
- ALS and other types of motor neuron disease are characterised by the accumulation and abnormal assembly of neurofilaments
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