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Section 11: Extracellular Macromolecules Fibrous proteins: keratin, collagen and elastin 02/21/06.

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Presentation on theme: "Section 11: Extracellular Macromolecules Fibrous proteins: keratin, collagen and elastin 02/21/06."— Presentation transcript:

1 Section 11: Extracellular Macromolecules Fibrous proteins: keratin, collagen and elastin 02/21/06

2 Selected Extracellular and Cytoskeletal Proteins Connective Tissue Fibrous Proteins –collagen –elastin –keratin –fibronectin Other Fibrous Proteins –fibrin –myosin (partially) Cytoskeleton Proteins –actin –keratin –intermediate filaments –microtubules Connective Tissue Fibrous Proteins –collagen –elastin –keratin –fibronectin Other Fibrous Proteins –fibrin –myosin (partially) Cytoskeleton Proteins –actin –keratin –intermediate filaments –microtubules 1

3 Cell Adhesion Receptors and Integrin are transmembrane proteins 2

4 Cell adhesion proteins Laminin Fibronectin © 2000 by Geoffrey M. Cooper Integrin 3 A chain Collagen binding B2 chainB1 chain Cell binding Cell binding Enactin binding Proteoglycan binding Collagen binding Cell binding Proteoglycan binding Matrix binding Actin Integrin Extracellular matrix Plasma membrane

5 Association Between Cell and Extracellular Matrix Some of the fibrous proteins are transmembane and connect (and communicate) to the cytoskeleton (actin, keratin, microtubule, tailin, vinculin). Fig. 11-22, Lehninger. Some of the fibrous proteins are transmembane and connect (and communicate) to the cytoskeleton (actin, keratin, microtubule, tailin, vinculin). Fig. 11-22, Lehninger. 4

6 Elastin Elastin (64-66kD) is rich in prolines and non-polar side chains, and one third of its amino acids are glycine. As a result, its has uncommon secondary structure (more random structure than found in other proteins). It does not have a stable tertiary structure. Elastin is very resilient. It can be stretched to lengths many times greater than in its relaxed state. It can also be compressed. Elastin is common in many connective tissues, along with collagen, especially if the tissue undergoes physical stress. It surrounds arteries, is in the lung and in ligaments. Elastin (64-66kD) is rich in prolines and non-polar side chains, and one third of its amino acids are glycine. As a result, its has uncommon secondary structure (more random structure than found in other proteins). It does not have a stable tertiary structure. Elastin is very resilient. It can be stretched to lengths many times greater than in its relaxed state. It can also be compressed. Elastin is common in many connective tissues, along with collagen, especially if the tissue undergoes physical stress. It surrounds arteries, is in the lung and in ligaments. 5

7 Elastin Structure and Function Elastin interconverts between a number of conformations, both disordered (upper two on left) and  -spiral (bottom left). After cross-linking, when elastin is stretched (or compressed) it is less stable and it returns to the disordered conformations. Elastin interconverts between a number of conformations, both disordered (upper two on left) and  -spiral (bottom left). After cross-linking, when elastin is stretched (or compressed) it is less stable and it returns to the disordered conformations. 6 (Fig. 4-28, Rawn) (Fig. 4-30, Rawn)

8 Elastin Cross-linking Some lysine residues in elastin are deaminated and oxidized to the aldehyde level. They combine with each other and with other lysines to form lysinonorleucine and desmosine cross-links Some lysine residues in elastin are deaminated and oxidized to the aldehyde level. They combine with each other and with other lysines to form lysinonorleucine and desmosine cross-links 7

9 Keratin Keratin is rich in cysteines. Its secondary structure is mostly  -helical. The helices form coiled coils (on right). The coiled coils pack into higher order elongated structures. Keratin properties depend strongly on the degree of disulfide cross-linking. –With low levels of cross-linking, it is flexible (hair, skin). –It can be made very hard with additional cross-linking (claws, horns). Extracellular via whithering of keratin-filled cells. Intracellular: cytoskeletal intermediate filaments. Keratin is rich in cysteines. Its secondary structure is mostly  -helical. The helices form coiled coils (on right). The coiled coils pack into higher order elongated structures. Keratin properties depend strongly on the degree of disulfide cross-linking. –With low levels of cross-linking, it is flexible (hair, skin). –It can be made very hard with additional cross-linking (claws, horns). Extracellular via whithering of keratin-filled cells. Intracellular: cytoskeletal intermediate filaments. Fig. 3.34 8 2 nm

10 Keratin Supramolecular Structure Two coiled coils bind together to form a protofibril (below). Protofibrils assemble into various microfibrils (on the right). Two coiled coils bind together to form a protofibril (below). Protofibrils assemble into various microfibrils (on the right).  Fig. 4-5 Fig. 4-6  Rawn 9

11 Keratin Cross-linking The structure of keratin is strengthened by disulfide cross-links from one helix to another. 10

12 Collagen Types Fibrils – long triple helices I. Skin, tendon, bone, dentin II. Cartilage and vitreous humor III. Skin, muscles, blood vessels (frequently found with type I) V. Fetal tissues, placenta, interstitial tissues XI. Cartilage Fibril associated – interrupted triple helices IX. Cartilage, vitreous, humor XII. Embryonic skin and tendons XIV. Fetal skin and tendons Fibril associated -- beaded VI. Most interstitial tissues Sheets IV. All basal laminae VIII. Endothelial cells, X. Cartilage growth plate Fibrils – long triple helices I. Skin, tendon, bone, dentin II. Cartilage and vitreous humor III. Skin, muscles, blood vessels (frequently found with type I) V. Fetal tissues, placenta, interstitial tissues XI. Cartilage Fibril associated – interrupted triple helices IX. Cartilage, vitreous, humor XII. Embryonic skin and tendons XIV. Fetal skin and tendons Fibril associated -- beaded VI. Most interstitial tissues Sheets IV. All basal laminae VIII. Endothelial cells, X. Cartilage growth plate 11

13 Collagen Collagen has glycine in every third position, is rich in proline, and contains hydroxyproline and hydroxylysine residues. Collagen does not have secondary structure, but three highly extended strands interact to form a triple helix. Collagen triple helices form a rod-like fibril or sheet aggregate that is somewhat flexible, not extensible, and can be very strong. Cross-linking increases its strength. It is common to connective tissue and is present in bone, dentin and cementum. Collagen is the most abundant protein in the biosphere. Collagen has glycine in every third position, is rich in proline, and contains hydroxyproline and hydroxylysine residues. Collagen does not have secondary structure, but three highly extended strands interact to form a triple helix. Collagen triple helices form a rod-like fibril or sheet aggregate that is somewhat flexible, not extensible, and can be very strong. Cross-linking increases its strength. It is common to connective tissue and is present in bone, dentin and cementum. Collagen is the most abundant protein in the biosphere. 12

14 Collagen Triple Helix Prolines, especially hydroxylated prolines, keep the individual chains extended, and increase Tm (keep it above body temperature). The small size of the glycine sidechain in every third position allows the three strands to come close together. There are interstrand hydrogen bonds. It is not very extensible because it is already extended (3.1 D per residue vs 1.5 D for  -helix). Glycosylation of hydroxylysines appear to modulate fibril or sheet formation by the triple helices. Prolines, especially hydroxylated prolines, keep the individual chains extended, and increase Tm (keep it above body temperature). The small size of the glycine sidechain in every third position allows the three strands to come close together. There are interstrand hydrogen bonds. It is not very extensible because it is already extended (3.1 D per residue vs 1.5 D for  -helix). Glycosylation of hydroxylysines appear to modulate fibril or sheet formation by the triple helices. Fig. 11-5 Stryer 3rd 13

15 Collagen Amino Acid Modifications Hydroxyprolines form interstrand hydrogen bonds. These post-translational modifications require ascorbate to reverse the prolyl hydroxylase active site Fe(III)-O -. Hydroxyprolines form interstrand hydrogen bonds. These post-translational modifications require ascorbate to reverse the prolyl hydroxylase active site Fe(III)-O -. 14

16 Glycosylation of Hydroxylysine The hydroxylysines are modified by sequential glycosylations, giving lysyl-gal-(  1  2)-glc  Activated sugar complexes are usually UDP-sugars. Higher levels of glycosylation favor formation of sheet structures by the collagen triple helices. The hydroxylysines are modified by sequential glycosylations, giving lysyl-gal-(  1  2)-glc  Activated sugar complexes are usually UDP-sugars. Higher levels of glycosylation favor formation of sheet structures by the collagen triple helices. 15

17 Procollagen and Tropocollagen Formation The three strands of procollagen are cross-linked by disulfide bonds near the C-terminal end, initiating triple helix formation. Procollagen is soluble, but tropocollagen, formed by hydrolyzing away peptide fragments at both ends, is not. The three strands of procollagen are cross-linked by disulfide bonds near the C-terminal end, initiating triple helix formation. Procollagen is soluble, but tropocollagen, formed by hydrolyzing away peptide fragments at both ends, is not. Fig. 4-24 Rawn 16

18 Aggregation and Cross-linking Tropocollagen spontaneously aggregates into elongated staggered arrays, shown in two dimensions at right. Hydroxylysine glycosylation determines fibril or sheet formation. Cross-linking strengthens the structure (lower). In bone, dentin and cementum, biomineralization begins in the gaps (hole zones) between the individual tropocollagens (type I). Tropocollagen spontaneously aggregates into elongated staggered arrays, shown in two dimensions at right. Hydroxylysine glycosylation determines fibril or sheet formation. Cross-linking strengthens the structure (lower). In bone, dentin and cementum, biomineralization begins in the gaps (hole zones) between the individual tropocollagens (type I). Fig. 4-24, Rawn 17

19 Collagen Cross-linking Lysines and hydroxylysines are used in cross-linking. Other than oxidation to the aldehyde level, the reactions appear to be non-enzymatic. Lysines and hydroxylysines are used in cross-linking. Other than oxidation to the aldehyde level, the reactions appear to be non-enzymatic. 18

20 Fibroblast to Mature Collagen Fiber Procollagen in vesicles is transported to the cell membrane in vesicles, and then secreted via exocytosis. Proteolysis, assembly, and lysine oxidation leading to cross-linking occurs outside the cell. Procollagen in vesicles is transported to the cell membrane in vesicles, and then secreted via exocytosis. Proteolysis, assembly, and lysine oxidation leading to cross-linking occurs outside the cell. 19

21 Collagen Degradation Collagenase cuts the 1000 aa triple helix into 250 and 750 aa fragments which melt and are proteolyzed. Some animal tissues (for example tadpole tails) have collagenases that are used to degrade collagen during growth and remodeling. The collagenase of Clostridium histolyticum destroys host connective tissue, helping to make it a highly invasive bacterium. In periodontal disease, host collagenases help break down periodontal ligament (collagens type I and III). Collagenase cuts the 1000 aa triple helix into 250 and 750 aa fragments which melt and are proteolyzed. Some animal tissues (for example tadpole tails) have collagenases that are used to degrade collagen during growth and remodeling. The collagenase of Clostridium histolyticum destroys host connective tissue, helping to make it a highly invasive bacterium. In periodontal disease, host collagenases help break down periodontal ligament (collagens type I and III). 20

22 Next topic: Section 12: Mineralized tissues. Calcium and phosphate metabolism Next topic: Section 12: Mineralized tissues. Calcium and phosphate metabolism


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