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111 Cards in this Set
- Front
- Back
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What is an Extracellular Matrix?
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A complex of non-living macromolecules manufactured by tissue cells and exported into the extracellular space.
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2 constituents of ECM:
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-Ground substance
-Embedded fibers |
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Function of ground substance:
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Resists forces of compression
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Function of Embedded fibers:
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Withstands tensile forces
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2 Components of Ground Substance:
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1. GAGs
2. Proteoglycans |
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GAGs:
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Unbranched polysaccharide chains of repeating disaccharide units.
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Proteoglycans:
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A core protein linked to many GAGs
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2 types of Fibers embedded in the ECM:
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-Collagen
-Elastin |
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Collagens
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Family of proteins made of a triple helix of alpha helices.
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Elastic fibers are made of:
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Crosslinked elastin molecules
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What coats elastic fibers?
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Fibrillin
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How are cells linked to the ECM?
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Via adhesive glycoproteins and integrins
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What adhesive glycoproteins are found in ECM?
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-Laminin
-Fibronectin |
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Basal Lamina
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Felt-like cell rug excreted by epithelial and muscle cells
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Define "Ground Substance"
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An amorphous gel-like material made of GAGs and proteoglycans
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What are the common sugars in the disaccharide repeats in GAGs?
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1. N-acetylglucosamine or
N-acetylgalactosamine One of above linked to: 2. Glucuronic or Iduronic acid |
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General chemical nature of GAGs:
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Negatively charged - b/c amino sugars typically are sulfated and have carboxyl groups attached to them.
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Result of GAGs being negatively charged:
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Na+ binds and osmotially attracts water into the matrix.
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Functional role of GAGs:
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Serve as a porous, hydrated, gel-like cushion to absorb and disperse compressive loads
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4 Main types of GAGs:
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1. Hyaluronate
2. Chondroitin/dermatan SO4 3. Heparan sulfate / heparin 4. Keratan sulfate |
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Function of Hyaluronate
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Predominant GAG in loose supporting tissues
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How is Hyaluronate different from other GAGs?
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-Nonsulfated
-Single disacch unit in long chains of 300-25,000 units -No covalent bonds w/ proteins |
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What are Proteoglycans?
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A core protein with covalently bound GAGs other than hyaluronate
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Where does attachment of GAGs to core protein occur?
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In golgi
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What is an Aggregan proteoglycan?
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Lg multimeric complex of many proteoglycans bound via link proteins to hyaluronate backbone.
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Where are Aggregan proteoglycans found?
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-Cartilage
-Connective tissue |
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What is the predominant Function of Proteoglycans?
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-Molecular filters - screen & retard macromolecules passing through them.
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Where is Heparan sulfate proteoglycan found?
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In the renal glomerular basal lamina - acting as a molecular filter.
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Other than filtering, how do proteoglycans function?
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Contain binding sites for
-secreted growth factors (FGF and TGFbeta) -Proteases -Protease inhibitors |
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What is the effect of ligands binding to GF and enzyme receptors on proteoglycans?
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Either inhibition or enhancement of the ligands' functions by preventing from reaching destination, or concentrating in spcf area.
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What is Syndecan?
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A proteoglycan that remains attached to a cell membrane instead of being secreted into ECM.
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What allows Syndecan to remain attached to the cell membrane?
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The core protein serves as the transmembrane protein.
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What does the core protein transmemb component attach to?
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-Actin filaments of the cytoskeleton
-Collagen/fibronectin of ECM |
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How do Syndecans function in fibroblasts?
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Bind FGF and present it to the cell membrane's FGF receptors.
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Why is it good for Syndecan to present FGF to its receptor?
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B/c it concentrates FGF at the membrane.
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What is the Proteoglycan genetic disease?
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Progeria syndrome
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What is Progeria syndrome?
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A fatal premature aging disorder
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What is the pathology in Progeria syndrome?
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Galactosyltransferase in fibroblasts is thermolabile and Dermatan SO4 chains fail to attach to proteoglycan.
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What makes up the ECM in addition to proteoglycans? What is it in ECM for?
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Fibers - to provide tensile strength and elasticity.
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What is the predominant fiber in ECM?
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Collagen
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What else is Collagen a predominant component of?
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The total mammalian protein mass - it takes up 25%
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Where are collagens made?
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Connective tissue Fibroblasts synthesize and secrete collagens.
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What is the form of collagen when fibroblasts secrete it?
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Tropocollagen - a triple helix of 3 alpha helices.
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What is the primary AA sequence of Collagen like?
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Gly-X-Y
X = commonly proline Y = commonly hydroxyproline |
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What happens to Tropocollagen once it gets secreted?
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Polymerizes into collagen
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How many types of collagen are there?
How many do we need to know? |
19
7 |
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What is the predominant type of collagen? How much?
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Type I - 90% of collagens
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What are the 3 different groups of Collagen?
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-Fibril forming
-Fibril associated -Network forming |
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Which collagens are Fibril forming?
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1,2,3
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So the polymerized form of the fibril forming collagens is?
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Fibril
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What are the Fibril-associated collagens?
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9, 12
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What is the polymerized form of fibril-associated collagens?
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Lateral association
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In what tissues are Collagens 9 and 12 found?
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9 = Cartilage
12 = Tendon/ligaments |
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Which collagens are Network-forming?
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4, 7
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What is the polymerized form of Collagen type 4? Where is it distributed?
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Sheetlike network found in basal laminae
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What is the polymerized form of Collagen type 7? Where is it distributed?
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Anchoring fibrils found in skin.
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In what organelle of fibroblasts is collagen made?
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Rough ER
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In what form is the product of RER during collagen synthesis?
What is it like? |
Preprocollagen - alpha helixes that still have their N/C terminals
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What does Preprocollagen undergo?
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Hydroxylation and glycosylation of Lys and Pro residues
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What happens after glycosylation/hydrolyxation of Preprocollagen?
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Alignment and assembly into the procollagen triple helix
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What happens after Procollagen is made?
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-Vesicular secretion to the cell surface via the golgi
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What is the first thing that happens to procollagen after secretion?
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-Cleavage of propeptides
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Product of propeptide cleavage from procollagen:
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Tropocollagen
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What happens to Tropocollagen?
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Spontaneous assembly in head-to-tail fashion to make collagen fibrils like 1/2/3/7
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What stabilizes the collagen fibril structure?
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Covalent bonding of neighboring lysine and hydroxylysine residues.
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What happens to collagen fibrils?
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They aggregate into collagen fibers
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What helps formation of collagen fibers?
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Fibril-associated Collagens type 9 and 12
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What characteristics of collagen fibrils are regulated by fibroblasts?
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-Orientation
-Size (length/diameter) |
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How are collagen fibrils oriented? How is it achieved?
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-Along the axis of tension
-Fibroblast cytoskeletons are aligned along it, and orient vesicle secretion that way. |
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What are 2 nongenetic diseases associated with collagen?
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1. Scurvy
2. Keloid |
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What is Scurvy?
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Vit C deficiency that prevents hydroxylation of Pro and Lys residues - decreased stability of collagens.
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Symptoms of Scurvy:
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-Fragile blood vessels
-Poor wound healing -Loose teeth in sockets |
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What is Keloid?
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Excessive accumulation of collagen during wound healing
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Symptom of Keloid
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Elevated scar
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4 Genetic Collagen Diseases:
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1. Osteogenesis imperfecta
2. Chondrodysplasia 3. Ehlers danlos 4. Defective Type VII collagen |
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Osteogenesis imperfecta:
-collagen type -symptom |
Type I
Easily fractured bones |
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Chondrodysplasia:
-collagen type -symptom |
Type II
Cartilage joint deformities |
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Ehlers-Danlos
-collagen type -symptom |
Type III
Weak skin, fragile vessels, Hypermobility of Joints |
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Defective type VII collagen:
-collagen type -symptom |
Type VII
Blistering skin Dystrophic necrosis of skeletal muscle |
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What fibers OTHER than collagen are found in ECM?
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Elastic
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In what 3 tissues is Elastic fiber particularly important?
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-Skin
-Lung -Blood vessels |
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What proteins compose elastic fibers? (2)
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-Elastin
-Fibrillin |
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What are Elastin chains like structurally?
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-Rich in gly/lys/proline
-Covalently linked by Lys residues |
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Where is Elastin made?
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In fibroblasts
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What do elastic fibers consist of?
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Elastin center surrounded by the glycoprotein FIBRILLIN.
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What syndrome is the result of mutations in Fibrillin gene?
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Marfan's
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What is the symptom of Marfan's?
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Ruptured aneurysms at the aortic root - due to lack of elasticity.
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What are the Adhesive glycoproteins in the ECM? What is their function?
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Fibronectin + Laminin
-Bound to ECM via specific binding sites on them, they link the ECM to cells |
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What are integrins?
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Transmembrane proteins that serve as cell "receptors" for the ECM - by binding integrin/laminin.
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What are integrins composed of?
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Heterodimers - a + B subunits
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What end of integrins is linked to the ECM?
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Amino end
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What is the carboxyl end of integrins bound to?
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Actin filaments in the cytoskeleton
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What are the Integrins that bind fibronectin and laminin called?
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Fibronectin or Laminin receptors.
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What is the structure of Fibronectin like?
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-Lg heterodimer glycoprotein with Disulfide linkages
-Binding sites for collagin, heparin, and integrins. |
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What is the sequence of the cell-binding site on Fibronectin? What binds to this site?
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RGD - ARg/Gly/Asp
-Integrin on the cell is what binds to this site on Fibronectin to connect the cell to ECM. |
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Where is laminin important?
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In linking the basal lamina to cell membranes.
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What is the Basal lamina?
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A sheetlike network of ECM proteins that interfaces epithelia and nearby CT.
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What 4 things compose the basal lamina?
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1. Type IV Collagen
2. Perlecan heparan sulfate 3. Laminin 4. Entactin |
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What are the 3 main functions of the basal lamina?
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1. Molecular filter
2. Selective barrier to cells 3. Scaffold for regeneration |
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What is a good example of how the basement membrane acts as a molecular filter?
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At the glomerular filter where the predominant proteoglycan is Heparan sulfate
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How does the basal lamina serve as a scaffold for regeneration?
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Skeletal muscle myoblasts migrate along BM to orchestrate myofiber regeneration.
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To what is BM tethered on its:
-ECM side -Cell side |
ECM side: fibrillar collagens (type VII)
Cell side: integrins via laminin |
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What cells can't penetrate basal lamina?
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-Fibroblasts
-Endothelial cells |
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What cells can penetrate the basal lamina?
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-Macrophages
-Lymphocytes -Nerve fibers |
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How do cells penetrate the BM?
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Via release of collagenases and serine proteases
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What enzyme is essential in degrading BM for cell traversal?
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Plasminogen
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What 2 molecules are the regulators of matrix degradation?
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-TIMPS
-SERPINS |
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TIMP:
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tissue inhibitor of metalloproteinase
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SERPINS
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Serine protease inhibitor
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What happens when skin epithelial cells break through the BM?
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Tissue metastasis of malignant melanoma cells.
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When do endothelial cells penetrate the ECM? How?
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During angiogenesis - by secreting hyaluronidase and plasminogen activator.
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