3.7 - 3.9 Integrating cells into tissues Flashcards

1
Q

What are tissues?

A

Cells in most multicellualr organisms are arranged into tissues. Tissues are cooperative assemblies of cells and the extracellular matrix

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2
Q

What are organs?

A

Cooperative assemblies of tissues

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3
Q

What are the 5 major types of tissue?

A
  • Epithelial
  • Connective
  • Nervous
  • Muscle
  • Blood and lymphoid tissues
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4
Q

What are the key characteristics of epithelial tissue?

A
  • Cells intimately connected to each other (junctions)
  • Apico-basal polarity
  • Little extracellular matrix (basement membrane)
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5
Q

What are the key characteristics of connective tissue?

A
  • Cells have few contacts with each other
  • No apico-basal polarity
  • Large amount of extra cellular matrix
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6
Q

What is nervous tissue?

A

Specialised, electrochemical signalling

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7
Q

What is muscle tissue?

A

Specialised, contractile

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8
Q

How are all tissue types seen in an organ such as the gut?

A
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9
Q

What do the epithelia line?

A
  • External body surfaces
  • Internal body cavities
  • Tube organs that communicate with exterior (alimentary, genito-urinary and respiratory tracts)
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10
Q

What does the epithelia form?

A
  • Secretory parts of glands and their ducts
  • Receptors for centain sensory organs
  • Even the brain arises from an epithelium (neuroectoderm) in the embryo
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11
Q

Name these epithelia

A
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12
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13
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14
Q

What are the functions of the epithelia?

A
  • Protection from mechanical and environmental insults
    • Lining of internal tube organs (oviduct and respiratory tracts)
    • Example: respiratory epithelium line air conducting tubes to lungs (infection risk)
    • Secrete mucus
    • Cell specialisation
      • Cilia
      • Goblet cells
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15
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16
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17
Q

How is a thick keratinised layer produced in the epidermis?

A
  • Epidermis starts as a stem cell on the basal laminar
  • Proliferates and differentiate to form keratinocytes that produce keratin and intermediate filaments
  • Modified cell death where they lose their nucleus and are just bags of keratin protein
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18
Q

What happens in the respiratory epithelium if there is a genetic defect of cilia?

A
  • Genetic defect of cilia in dynein genes stops them from beating, as dynein are responsible for movement
  • Results in primary ciliary dyskinesia
  • Situs inversus, male infertility
  • Recurrent respiratory disease in children
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19
Q

What happens to the respiratory epithelium if there is a genetic defect of chloride channel?

A
  • Abnormal export from the ER
  • Causes cystic fibrosis
  • Mucus so thick that cilia can’t move it
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20
Q

What is the function of epithelia in the organs (intestine)?

A
  • Absorption from lumen of organs (intestinal tract and kidney tubules)
  • In the intestine there are villi
  • Further membrane specialisations in the microvilli (brush border)
  • Protect epithelium from acids by secreting mucus
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21
Q

What is the polarity of the gut epithelium which absorbs nutrient molecules?

A
  • It has apico-basal polarity and apical and basal membrane have different properties
  • Apical has active transport channel where there is increased glucose concentration in the cell
  • Basal has passive channel and transporter protein for diffusion of glucose to the blood
  • There are special cell-cell junctions that prevent backflow of molecules
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22
Q

How do the apical and basal membranes differ?

A
  • Apical is for absorption, secretion, specialisations (microvilli and cilia)
  • Basal is for adhesion to extracellular matrix and secretion into sub mucosa
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23
Q

What are the four different types of junctions for epithelial cells?

A
  • Tight junctions
  • Adherens junctions (desmosomes)
  • Gap juncitons
  • Focal contacts (hemidesmosomes)
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24
Q

How are cell junctions in epithelial cells usually aranged?

A
  • Cells may have more than one type of junction
  • Arranged in junctional complexes
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25
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What are tight junctions?
* Usually near the apical surface * They are bands of plasma membrane proteins encircling the cell * Prevent leakage of molecules across the epithelium * Separate different membrane domains of epithelium, essential to maintain cell apico-basal polarity
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What is the structure of tight junctions?
* Bands of membrane proteins, claudin and occludin, in adjoining cells * Proteins form very strong links, non covalent hydrogen bonds * More bands means more impermeability
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How permeable are tight junctions?
* Experiments with tracer molecules show how effective tight junctions are at preventing movement of molecules between cells. Permeability varies in different cell types
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What is the role of adherens junctions?
* They link epithelial cells to each other * Link with cell cytoskeleton rather than intermediate filaments through actin * They involve homophillic interactions between cell adhesion molecules called cadherins * E, P, N cadherins (classical)
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What are the interactions between adherens junctions?
* Cadherins are transmembrane proteins, made up of flexible extracellular domain * The flexibility is stabilised if you have Ca2+ so it extends into the extra-cellular space and adheres to each other via N-terminal cadherin repeat
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What other proteins are there in adherens junctions?
* Links to the actin cytoskeleton via linker/adaptor proteins * beta-catenin * alpha-catenin * p120 catenin * gamma-catenin * vinculin * Beta catenin also functions in growth factor signalling
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What is the funciton of adherens junctions in movement?
33
What is a prominent example of epithelial folding in development?
* Formation of neural tube * Notochord releases factors that stimulate infolding in neural tube * Change in cadherin as cells change their fate * Shows how cells change patterns of cadherin expression during tissue morphogenesis
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How do cadherins influence cell sorting?
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How is cadherin used in embryogenesis?
* Cells from different layers of an early amphibian embryo will sort according to their origins, * mesoderm (green), neural plate (blue), and epidermis (red) sort into a structure that resembles and embryo with a neural tube in the centre
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What do desmosomes do?
* they spot weld cells together * Distribute tensile forces * Inter-connect intermediate filaments of adjacent cells * Found in tissues subject to high mechanical stress such as the heart, muscle and epidermis
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What molecules interact in desmosomes?
* Link epithelial cells to each other via homophillic interactions between cell adhesion molecules of the cadherin family (desmoglein, desmocollin) * Non classical cadherins * Link with cytoskeleton (intermediate filaments) via adaptor proteins (plakoglobin, plakophillin, desmoplakin)
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How do desmosomes compare to adherens junctions with reference to the actin filaments?
* Actin filaments terminates while intermediate continutes to pass through
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What are the characteristics of intermediate filaments?
* Criss cross cell cytoplasm * Confer tensile strength * Intermediate filaments are often cells specific (desmin in the heart, keratin in the skin and other epithelia)
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How do desmosomes relate to autoimmune disease?
* Pemphigus vulgaris due to antibodies to desdemonal proteins which distrupt the desmosome * Causes skin and mucosal blistering as epidermis separates from dermis * Potentially fatal
42
How do desmosomes relate to congenital disease?
* Epidermolysis bullosa simplex due to mutations in keratins * Cuases skin and mucosal blistering * Potentially fatal
43
What linkages are involved in a focal linkage?
* Transmembrane adhesion proteins called integrins which bind extracellular matrix proteins * Link to actin cytoskeleton via adaptor proteins (vinculin, talin) * Involved in cell movements and attachment (myotendinous junction)
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How do focal adhesions generate cell traction forces?
* Interaction of integrins with their substrates plays an important role in cell motility via generation of cell traction forces (CTF) in combination with actin assembly and disassembly * Myosin interactions at the rear of the cell
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What are focal adhesions sites of anchorage for?
* Focal adhesions are sites of anchorage for intracellular actin filaments and extracellular ECM molecules * Also concentrate other signalling molecules, where phosphotyrosines at the integrin junction is phosphorylated for cell signalling
46
How is integrins an example of inside out signalling?
* Cells regulate the activity of cell surface integrins * Integrins will not engage extracellular matrix ligand unless activated * Example : growth factor receptor signal activates integrins via intracellular signalling * Talin curls up on itself, vinculin binding sites are open with permits actin to engage with integrins, talin also bind to beta subunit
47
How does outside-in signalling occur in integrins?
* Activation by inside out signals allows binding to extra cellular matrix ligand * Extra cellular matrix binding recruits intracellular protein kinases, vinculin, talin, filamin, alpha-actin * Multiple integrins recruited to focal adhesions gives signals into the cell
48
How is talin a tension sensor at cell-matrix junctions?
* It has multiple binding sites (vinculin, actin, integrins) * Tension stress from actin filaments reveals cryptic binding sites * stabilises vinculin and integrins in focal adhesions * Promotes signalling at focal adhesions * Tension stretches the extra cellular matrix causing growth factor release
49
What does this experiment show?
* It has an actin binding domain and vinculin binding domain * Fix talin to a glass slide via N terminal domain * Magnetic bead at the C terminal which stretches it out * Vinculin binding site exposed and vinculin binds * Putting tension on actin filaments
50
How is cell proliferation dependent on traction and distribution of growth factors?
* Integrins may act as mechanoreceptors * Tension on the cytoskeleton may combine with growth factor signalling to promote G1 progression * Cell with one spot dies as it cannot spread out and establish focal adhesions to set up signalling centre
51
How does outside in signalling with integrins require other kinases?
* Clusters of intergrins permit extracellular matrix signals to be transmitted but integrins have no kinase domains * Signalling events require other kinases such as focal adhesion kinase (FAK) * FAK activates the Ras Map kinase pathway * Integrins don't have kinase activity but by forming focal adhesion you can can activate signalling
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What are hemidesmosomes?
53
What integrins are involved in the skin in hemidesmosomes?
* alpha6beta4 integrins in hemidesmosomes adhere cells to the basement membrane * Link to intermediate filaments
54
What happens if there is gene knockout of hemidesmosome integrins in mice?
* Deletion of beta4 integrins means there are skin blisters * Failure of keratinocytes to adhere to basement membrane * Skin not attached to the dermis and separates with tension * Fatal resulting in neonatal death
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Summary table
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What can pass through a gap junction?
* Adjacent cell membranes are 2-4 nm apart * Allow small molecules such as ions, sugars, nucleotides, vitamins, singalling mediators (Ca2+, cAMP, IP3) to pass through cells with pore size 1.5 nm * Excludes macromolecules \> 1000 daltons (proteins, nucleic acids and polysaccharides)
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What are the channels between a gap junction?
* Channels (connexons) consist of 6 membrane spanning proteins (connexins) * Channels/connexons in register between two cells form the gap junction
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What are the functions of gap juncitons in these tissues?
61
What do connexin mutations lead to?
* Cx26 mutations commonest cause of congenital deafness
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Where is the connective tissue here?
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What is the extracellular matrix and its components?
* spaces between cells composed of a complex array of molecules * composed of tough fibrous proteins embedded in a polysaccharide gel-like material (ground substance)
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How does the extracellular matrix vary in conenctive tissues?
* Variety in connective tissues due to differences in composition and arrangement of extracellular matrix * Tendon has numberous fibrous proteins, little ground substance * Bone has calcified ground substance and fibrils * Cartilage has large amount of polysaccharide gel
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What are the roles of the extracellular matrix?
* Structural support * Regulation of cellular activities * Cell survival * Cell migration * Cell proliferation * cell shape * cell function
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What produces the extra cellular matrix?
* Extracellular matrix is produced by cells within it * Cells produce and secrete organic components of the extracellular matrix * Cells organise the extracellular matrix
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How do cells organise collagen in the extracellular matrix?
* Collagen fibres must be correctly aligned within tissues * Cells deposit and organise collagen matrices * Alternate layers of longitudinal and transversly sections fibres * Fibroblast organise and arrange that extracellular matrix
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Which cells produce extracellular matrix and in what tissues?
* Fibroblasts (loose connective tissue) * Osteoblasts(bone) * Chondroblasts(cartilage) * Epithelial cells (basement membrane in epithelia)
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What is the extracellular matrix broadly composed of?
* Proteins * Fibrous/structural such as collagen and elastin * Adhesive such as laminin * Proteoglycans which are carbohydrate modified proteins, very large molecules which attract water
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What are the characteristics of collagen in the extracellular matrix?
* About 25% of total protein mass in mammals * 42 different collagen genes with different properties * Provides tensile strength, can withstand stretching * Rich in proline and glycine arranged in repeats as an alpha helical polypeptide chain
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What is the structure of collagen?
* Collagen alpha chains composed of a series of Gly-X-Y triples where X is any amino acid, usually proline or lysine and Y is any amino acid usually hydroxy-proline or hydroxy-lysine * Collagen molecules consist of three alpha chains arranged in a super helix * Alpha chain is a left handed helix due to dihedral angle of prolines
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How are collagens arranged in fibrils?
* Many collagen molecules assemble together (covalent cross linking) to form collagen fibrils (10-300 nm in diameter) * Regular packing of collagen molecules leads to cross striations (67 nm periodicity)
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How do collagen fibres arrange themselves into fibrils?
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Which collagens form fibres?
* Only collagens I, II, III, V form fibrilar collagens * Collagen IV forms sheets * Collagens VI, IX, XII are fibril associated collagens which decorate fibrilar collagens and mediate fibril interactions
75
What is the structure of fibril associated collagens?
* Triple helix is interrupted by non helical domains giving flexibility * They are not cleaved after secretion so they retain polypeptides * They do no aggregate to form fibrils * Bind periodicially to other collagen fibrils * Type IX binds to II * Type XII to type I
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What are the steps of collagen synthesis before secretion?
1. Collagen precursors (procollagens) are synthesised into ER lumen 2. N and C terminal ends have propeptide 3. Intrachain disulfide bonds between N and C terminal propeptide sequences align chains to form triple helix in ER 4. Procollagen is modified in ER and Golgi (hydroxylated and glycosylated) and secreted by exocytosis
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What are the steps of collagen synthesis after secretion?
* After processing and assembly of 3 pro-alpha-chains, type I procollagen is secreted into the extracellular space * Extracellular enzymes (procollagen peptidases) remove N and C terminal propeptides so collagen self polymerises into fibrils * Collagen pro-peptides prevent premature assembly of collagen in side cells
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How does cross linking occur in collagen synthesis?
* After secretion covalent bonds (lysine residues) cross-link the collagen molecules, particularly in non-helical ends * Extent of cross-linking affects tensile strength. * Inhibition of cross-linking reduces tensile strength * Highest level of cross-linking occurs in tendon collagen (high tensile strength)
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What happens if there is a defect in collagen I?
* Osteogenesis imperfect (brittle bones) * Variety of mutations (col1A1, col1A2) * Glycine substitutions failure to form triple helices
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What happens if there is a defect in collagen II?
* Achondrogenesis (col2A1, GMAP210) * Failure in collagen synthesis or transport * Abnormal cartilage gives abnormal bone and joint formation which is severe
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What happens if there is a defect in collagen III?
* Ehlers Danlos syndrome * Fragile skin, blood vessels and hypermobile joints, elastic skin
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How is scurvy a defect in collagen synthesis?
Failure to hydroxylate prolines and lysines in fibrilar collagen due to reduced levels of ascorbate (vitamin C)
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What does elastin do?
* It provides elasticity to tissues (lungs, blood vessels) * It is the major protein in arteries * Forms covalently corss linked network of elastin molecules * With fibrillin it forms elastic fibres
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What happens in Williams-Beuren syndrome?
* Elastin is mutated giving supravalvular arotic stenosis, mental retardation, facial dysmorphoa
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How does the artery have arrangements of elastin and collagen?
* Elastic arteries such as the aorta undergo high pressure fluctuations * Need elastic fibres (elastin and fibrillin) for recoil of vessel wall * Collagen provides tensile strength and eleastin elasticity
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What happens if you have a detect in fibrillin I?
* Marfan syndrome * Large blood vessels with dilation of pulmonary artery and aorta resulting in aneurysms * Skeletal defects causing scoliosis from elastic fibres in elastic cartilage and growth plates * Dislocated lens as fibrils that hold lens are rich in elastin * Heart has mitral valve insufficiency (valves usually rich in elastic fibres)
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What are the two ways that cells can attach to the extra cellular matrix?
* Transiently and weakly. (Eg. migration) * Irreversibly and strongly. (Eg. Muscle and tendons).
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What are the 4 extracellular matrix proteins that mediate adhesion?
* Laminin * Fibronectin * Tenascin * Collagen
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What are the two forms of fibronectin?
* It is either a soluble dimer in plasma * Or insoluble cell-associated dimer with disulfide bonds. It requires integrins (RGD) or actin to form fibrillar fibronectin * Tension reveals cryptic binding sites to permit association between fibronectin molecules to form fibrils at adhesions
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What happens if you lose fibronectin via gene knockout?
* Embryonic lethal, no formation of blood vessels as endothelial cells fail to migrate or attach to basement membranes * Antibodies to RGD domains or RGD peptides inhibit cell attachmetn and migration * If you lose RGP peptides you inhibit cell from attaching as it will compete with RGD in fibronectin
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What is laminin?
* An adhesive extracellular matrix protein * Has 3 chains (alpha, beta, gamma) held together by disulphide bonds * Multiple different forms (5alpha, 3beta, 3 gamma) * Multiple binding domains to bind to cell (integrins) or to bind ot other extracellular matrix components
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Where are laminins found?
* Common in basement membranes * Interact with collagens, nidogen and perlecan * Interact with integrins on cell surfac
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What happens if you knockout laminin gamma1 chain/ other mutations?
* Knockout of laminin gamma1 chain is embryonic lethal as you fail to form a basement membrane * Mutations include; * Epidermolysis bullosa (LAMC2, LAMA3) * Muscular dystrophy (LAMA2) * Neuromuscular disorder (LAMB2)
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What are basement membranes?
* They are specialised extracellular matrix * Underlies epithelium cells and tubular structures, separting epithelia and connective tissue * Synthesised by cells that rest upon it
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Is the basement membrane inert?
* Not inert * Contains growth factors * Can modulate cell behaviours
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What is the structure of proteoglycans?
* large protein core linked to negatively charged chains of polysaccharides (due to carboxyl and sulfate groups) * Glycosaminoglycans * Consist of disaccharide repeats
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What do proteoglycans do in the extracellular matrix?
* Serve complimentary function to collagens * Form gel-like ground substance * Resist compressive forces * Permit diffusion of nutrients, metabolites, hormones and growth factors
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How are proteoglycans linked?
* Multiple GAG chains are linked to a core protein (serine residues) via linker tetrasaccharides. * Need to connect to polypeptide chain of core protein * Link tetrasaccharide links to disaccharide repeat via serine amino acid
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What is the size of proteoglycans and how does it compare to glycoprotein?
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What are the very large aggregates of proteoglycans known as?
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How do proteoglycans form gels?
* negative charge attracts cations such as Na+ * Forms gels due to water following ion concentration * Osmotic pressure gives resistance to compression with balances tensile strength of colalgen * Form \<10% of dry weight of fibrous protein but may occupy 90% of space.
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What is the role of proteoglycans in signalling?
* Can bind and regulate activity of secreted proteins such as growth factors * Sequester from cells (inhibit signalling) * Present to cells (enhance signalling) * Increase diffusion capacity of growth factors (enhance signalling)
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