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Cytoskeleton
Organisation of the Body
| Question | Answer |
|---|---|
| Why do we need a cytoskeleton | Movement - cell motility and shape regulation Cellular organisation - moving organelles around a cell and vesicle transport for secretion Structure - mechanical strength |
| 3 major protein filaments in the cytoskeleton | Microfilaments Microtubules Intermediate fibres |
| Actin filaments (microfilaments) | 5-7 nm in diameter 2 stranded helical polymers of actin. Alpha form in muscle, beta and gamma in other cells. Linear bundles form 2 and 3D networks through the cell concentrated just below the membrane.These determine cell shape and allow cell movement |
| Structure of Actin filaments | Flexible actin filaments made of actin monomers These have structural polarity - plus end has faster growth and shrinkage, growth is favoured Minus end - slower growth and shrinkage, shortening is favoured which shows treadmilling |
| How does actin allow cells to move | Rapid addition and removal of small soluble units and large filamentous polymers. Can be removed from one end and added to the other, extending the cell in that direction. Allows movement towards chemo-attractant, nutrient source, antigen etc |
| Cytoskeleton allowing neutrophils to move | These detect bacteria by sensing chemo-attractant which polarises the cell. They advance by extending the protruding actin filament structure to give a crawling cell. They then engulf the bacteria by phagocytosis |
| Actin filaments in axon growth cones | Growth cone extensions (filopodia) contain actin filaments. These are highly dynamic and grow in response to a stimuli, the membrane protrusions created are supported by polymerisation of actin filaments. |
| Actin and Myosin in muscle movement | Myosin thick filaments use motors in head domain to slide along actin thin filaments. Myofibrils use actin and myosin for motility. Evidence comes from fluorescent microscopy showing actin filaments moving across the slide |
| Microtubules | 25 nm in diameter Long hollow cylinders made of proteins alpha and beta tubulin. These are ridged and straight to direct movement of intracellular transport e.g. organelles, vesicles and chromosomes They connect at the microtubule organising centre |
| What are microtubules made of | Tubulin heterodimers: beta and alpha tuberin to form a microtubule subunit. These grow faster at the plus end, whilst hydrolysis is faster at the minus end, allowing them to spread through the cell |
| What is dynamic instability of microtubules | Microtubules convert between shrinking and growing rapidly GTP favours growth GDP favours shrinkage |
| What is treadmilling | Subunits recruited at plus end and lost at minus end. These subunits cycle whilst length remains the same. This is a very active, energy expensive process but allows spatial and temporal flexibility in the structure |
| Microtubule Organising Centres | Microtubules radiate out from MTOCs, with the stable end embedded here The dynamic plus end is free in cytoplasm for growth and shrinkage (control is all at one end) Most animal cells have a MTOC known as the centrosome |
| How do organelles move withing the cell | Organelles move along microtubules in the presence of ATP. They provide "tram tracks" for movement Kinesin motors move towards plus end Dynein motors move towards minus end Movement can be uni or bi directional |
| How microtubule organisation differs across cells | Fibroblast - all head out from MTOC Neuron axon - microtubule plus end at synapses, minus end in cell body Transport down long axons - degeneration and starvation of axon terminals. Vesicles at synapses transported along microtubules |
| Microtubule associated proteins | MAP 2 and MAP tau bind to and stabilise microtubules to enhance stability and allow for longer, less dynamic tubules Kinesin 13 bind to microtubules and destabilises them, increasing frequency of catastrophes leading to shorter, more dynamic tubules |
| Role of microtubules in cell division | Cell division is controlled by complex interaction of motor proteins and the microtubule cytoskeleton. The centrosome replicates, so two minus ends are present. The microtubules bind to chromosomes to link the centrosome to the kinetochores |
| How do microtubules and dynein drive motility | Flagella have a undulating movement. Cilia beat in waves to move fluid. The axoneme is the 9+2 arrangement of cilia and flagella. The motor protein dynein (between cilia) walks along the microtubule to bend axoneme, allowing for movement of these |
| Example of disease from mutations in ciliary dynein | Kartagener's syndrome is due to a mutation in ciliary dynein, so cilia and flagella cannot beat normally. This leads to infertility, lung infections, left/right asymmetry deficit |
| Effect of tubulin mutations | alpha tubulin mutations cause impaired neuronal migration in mice and lissencephaly in humans (abnormal brain development) Beta tubulin mutations cause a cortical malformation in the brain This connects to tubulins role in making axons |
| Roles of microtubule associated proteins in development | 6 MAPT isoforms caused by alternative splicing of exons 2,3,10. Shortest form- binds microtubules more weakly. Expressed in the embryo to allow neuronal plasticity Longest form- binds microtubules more strongly. Expressed in adults for neuronal stability |
| Intermediate filaments | 10-12 nm diameter Provide mechanical strength and structure These consist of multimers twisted into rope link filaments (tend to be tetramers) E.g. keratin (epithelia), Desmin (muscle), Neurofilament and Nuclear lamin proteins |
| Keratin filaments in epithelial cells | 20 types in epithelial cells with 10 more specific to hair and nails The networks are held by disulphide bonds, so mutations in keratin can lead to skin blistering as the epidermis is not attached properly so it detaches from the dermis. |
| Neurofilaments in neurons and axons | 3 types- light, medium and heavy These form cross links to provide axons with tensile strength. The level on NF gene expression controls axon diameter - larger axon has a hight velocity of conduction due to more NF present |
| Lamins provide structure to the nucleus | 3 Types A B C These form the nuclear lamina, a meshwork of intermediate filaments lining the inside of the inner nuclear membrane. This determines nuclear shape and provides an anchoring point for chromosomes and proteins in nuclear pores. |
| Drugs which target actin and tubulin filament formation | Toxins produced by plant and fungi to prevent being eaten Specifically target dividing cells as microtubules are key to cell division e.g. Taxol to treat cancer Useful lab agents to investigate processes e.g. nocodazole to prevent transport |
| 4 types of cell-cell junctions | Anchoring junctions Tight junctions Gap junctions Synapses |
| Anchoring junctions | These can attach to actin or IF Actin - adherens junctions (cell-to-cell) or actin linked cell matrix adhesions (cell to extracellular matrix) IF - desmosomes (cell-to-cell) or hemidesmosomes (cell to extracellular matrix) These tend to be more stable |
| Role of anchoring junctions | Structural to hold cells together. they spot weld cells together They connect to the intermediate filament depending on type e.g. keratin in epithelial cells |
| Molecular components of desmosomes | These adhere cells together. Intermediate filaments attach to desmosomes on the inside of the cell via anchor proteins. Adhesion proteins (e.g. cadherins) hold junctions together, they stick out the cell surface to increase strength of connection |
| Anchoring junctions in the skin | Keratin filaments cross the cytoplasm and connect desmosomes which link cells together, with keratin as an intermediate filament. Desmosomes hold prickle cells together, these are linked the the IM cytoskeleton |
| Genetic mutations in adherent junctions | Junctional EB - recessive mutations in integrin alpha 6 and beta 4 and collagen XVII lead to epidermolysis bullosa, the blistering of the skin due to the loss of cell-basement membrane adherence EB simplex - dominant mutations in keratins 5 and 14 |
| Tight Junctions | Highly dynamic seal that constantly adjusts the degree of paracellular permeability. These are a barrier to harmful luminal contents in the intestines but allow uptake of nutrients and drugs. The permeability changes depending on the type of tissue |
| Pathologies affecting tight junction permeability | Chron's disease makes tight junctions more permeable |
| Structure of tight junctions | TEM of routine thin sections show where tight junctions are found. Fusion ridges are where two membranes of each cell meet and fuse, looking ridged. Fusion ridges bind cells together and affect leakiness of the epithelial layer. More ridges = less leaky |
| How tight are tight junctions | Tightness can be of varying flexibility: small intestine between epithelial cells is less tight then in the blood brain barrier between capillary endothelial cells We can generate distinct apical and basolateral domains using tight junctions |
| Tight junctions and cellular transport | These confine transport proteins to domains, generating apical and basolateral domains. e.g. in epithelial cells sodium ion coupled glucose transport occurs on the apical surface and facilitated diffusion of glucose occurs on the basolateral membrane |
| Transcellular and Paracellular | Transcellular - across the cell e.g. glucose Paracellular - between cells through tight junctions |
| Gap junctions | Bridge gaps between cells to connect them and allow substances to cross. This couples cells electrically and metabolically. Cells only exchange small molecules e.g. sugars, amino acids, nucleotides not macromolecules e.g. polysaccharides, proteins |
| Structure of Gap junctions | Made of connexins - four pass transmembrane proteins. 6 connexins join to form a connexon. Two connexons (one in each membrane) meet to form an aqueous channel. These are dynamic with a half life of only a few hours, so continuous gene expression needed |
| Functions of Gap junctions | Electrical coupling of cells to synchronise activity e.g. of cardiac cells Sharing small metabolites to coordinate activity of neighbouring cells Embryogenesis - in early embryo cells are electrically coupled, they decouple as cells differentiate |
| How is gap junction permeability regulated | This is flexible and is controlled nu cellular pH and [Ca2+] |
| Gap junctions in disease | Connexin-26 mutations cause inherited skin disease and deafness. Vohwinkle syndrome and palmoplantar keratoderma - dominant genetic skin disease due to excessive formation of keratin. This also causes deafness due to disrupted flow of K+ in sensory cells |
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