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Specialized tissue Proteins:Collagen and Elastin

Specialized tissue Proteins:Collagen and Elastin. Dr.S.Chakravarty MBBS, MD. Learning objectives:. Describe the structure and formation of collagen and elastin List the various steps in Post translational modification of collagen

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Specialized tissue Proteins:Collagen and Elastin

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  1. Specialized tissue Proteins:Collagen and Elastin Dr.S.Chakravarty MBBS, MD

  2. Learning objectives: • Describe the structure and formation of collagen and elastin • List the various steps in Post translational modification of collagen • Mention the role of Vitamin C and copper in stabilizing the collagen structure • List the types of collagen and its distribution in the body • Describe the defects of collagen and elastin and its associated clinical conditions

  3. Extra cellular matrix: • Fibrous proteins – collagen, elastin • Specialised proteins – Laminin, Fibronectin • Gel forming – Proteoglycans

  4. Functions of extracellular matrix • Regulation of proliferation, differentiation, migration and cell-cell recognition • Prevents or limits the movement of bacteria and cancer cells • Damage leads to various diseases like osteoarthritis, Glomerulonephritis etc.

  5. Property of fibrous proteins • Alpha helical secondary structure. • Low water solubility • A long narrow rod like structure. • Role in determining cellular structure and function.

  6. Types of fibrous proteins: • Collagen - most abundant protein in body; rigid, insoluble. • Elastin - stretchy, rubber-like, lungs, walls of large blood vessels, ligaments • Keratin - tough fibers (hair, nails, outer epidermis)

  7. Collagen –many functions in many tissues !! • Dispersed as a gel – Vitreous humor • Tight parallel fibres – Tendons • Stacked for minimal scattering – Cornea • Mechanical shearing – Bone.

  8. Types of collagen:So far, 28 types of collagen have been identified and described. The five most common types are: Type I collagen is stronger than steel !!

  9. Structure of Collagen

  10. Outline • Molecular collagen (pre pro collagen and pro collagen) – soluble • Microfibrils – tropocollagen ( insoluble) • Fibrils • Fibres

  11. Collagen triple helix Left handed helix 3 such strands wound together

  12. About 25-30% of the total weight of body is collagen. • Major fibrous element of tissues like bone , teeth , tendons , cartilage and blood vessels. • Each polypeptide has about 1000 amino acid residues. • 1/3 of the a.a are Gly residues i.e every 3rd residue is glycine. • The repetitive a.a sequences can be denoted by Gly-X-Y , where X and Y are commonly Proline and Hydroxyproline .

  13. The collagen is a rod like structure . • The three polypeptide chains are held in a helical conformation by winding around each other.This results in formation of a superhelical cable with 3.3 amino acids per turn and each turn separated by 2.9 A. • The strands are H-bonded to each other ( H-donated by NH grp and H-accepted by C=O ) • Further stabilization by H –bonds between OH- groups and the bridging water molecules.

  14. Quarter staggered Arrangement • The trophocollagen molecules are arranged in in such a way that each row moves ¼ length over last row and the 5th row repeats the same position of the first row. • Molecules in each row separated by 400 A and adjacent and adjacent rows by 680 A. • The collagen fibres are further strengthened by covalent cross links b/w lysine and hydroxy-lysine

  15. An electron micrograph of collagen from skin

  16. Formation of pro alpha chains: Cytoplasm of fibroblasts Formation of pro alpha chains: with signal sequence at N-terminal ends. Rough-endoplasmic reticulum: signal sequence directs proteins to RER. Removal of signal sequence

  17. Events in the RER :Formation of pro-collagen • Hydroxylation of proline and lysine • Requires a dioxygenase with Fe . • (Vit C keeps the iron reduced ) • Glycosylation – hydroxylysine with glucose. • Spontaneous disulfide bond formation at C terminal peptides formation of triple helix. 3. Assembly in the Golgi and release of pro-collagen to extra cellular matrix. USMLE concept!

  18. 4. Extracellular matrix • Stabilizing force • H-bonding between Gly of one chain and Pro of another • ~1 H-bond per triplet • Extra cellular cleavage of N and C-terminal propeptides – pro collagen peptidases.

  19. Tropo collagen molecules: • Terminals (ends) of the triple-helix are different • C-telopeptides • N-telopeptides • Terminals are non-helical • Helps in triple helix formation • N-TERMINAL INTRACHAIN DISULPHIDE BONDS • C-TERMINAL- INTERCHAIN + INTRACHAIN DISULPHIDE BONDS (from Kadler, 1996)

  20. C-telopeptide Elevated levels can be used in the confirmation of increased bone turnover. Elevated levels can identify persons with osteoporosis who have elevated bone turnover and who, as a result, are at increased risk for rapid disease progression. The patient's response to antiresorptiveosteoporosis treatment can be monitored through this test. This test can be used to monitor and assess how effective antiresorptive therapy has been in patients treated for disorders such as osteopenia, osteoporosis, and Paget disease. This test can also serve as an adjunct means of monitoring patient response to other treatments for diseases with increased bone turnover, such as rickets, osteomalacia, and hyperthyroidism.

  21. Cross links formed by lysyl/prolyl oxidase • copper co-enzyme • Oxidative deamination of lysines and hydroxylysinesforms Allysine (aldehyde) • This reacts with amino group of nearby lysine or hydroxylysine to form interchain cross-link. • Very important for tensile strength of collagen. Cu2+/ vitamin B6 USMLE concept !

  22. Both extremes are bad !! • Excessive cross links problem in OLD AGE Hardening of ligaments (STIFF)Prone to tear • Less cross links  Weak collagen • Menke’s disease due to decreased Cu (discussed later)

  23. Covalent X-links between Allysine and hydroxylysine Tropocollagen molecule triple helix of a-chains.

  24. Molecular Cell Biology, 4th edition Harvey Lodish, Arnold Berk, S Lawrence Zipursky, Paul Matsudaira, David Baltimore, and James Darnell.

  25. Kaplan USMLE step 1 lecture notes

  26. Elastin • Helps in retaining the shape after stretching. • Connective tissue protein. • lungs, large blood vessels, elastic ligaments

  27. Elastic fibres • Outer cover - Microfibrils containing fibrillins and microfibril associated glycoproteins (15%) • Core of amorphous elastin –single polypeptide chain of 800 amino acids-85% • Non-polar amino acids – gly, ala, val. Also rich in pro, lysine. ( no OH-proline or OH-lysine)

  28. Elastin • 3D network of cross-linked polypeptides – (tropoelastin) • cross links involve Lys and alLys –lysyloxidase • 4 Lys can be cross-linked into desmosine • Desmosines account for elastic properties

  29. Elastin Structure and Function • Elastin interconverts between a number of conformations, both disordered (upper two on left) and b-spiral (bottom left). • After cross-linking, when elastin is stretched (or compressed) it is less stable and it returns to the disordered conformations. 6

  30. 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 USMLE concept ! 7

  31. Table 48–5. Major Differences Between Collagen and Elastin Collagen Elastin Many different genetic types One genetic type 2. Triple helix No triple helix; random coil conformations permitting stretching 3. (Gly-X-Y)n repeating structure No (Gly-X-Y)n repeating structure 4. Presence of hydroxylysine No hydroxylysine 5. Carbohydrate-containing No carbohydrate 6. Intramolecularaldol cross-links Intramoleculardesmosine cross-links 7. Presence of extension peptides No extension peptides present during biosynthesis during biosynthesis

  32. Degradation of elastin: • Serine type elastase: neutrophils, macrophages, fibrblasts. • Matrix metalloproteinases – mmp-12 and 7, gelatinases.

  33. Scurvy • Malaise , Lethargy • Poor wound healing • Bleeding gums • Weak bones • Petechiae over skin • Anaemia

  34. Vasco Di Gama 1498

  35. 1747, James Lind and the Limeys !!

  36. MCQ 1 • A culture of fibroblast cells is provided with equal all the 20 amino acids. After 10 days , the concentration of the amino acids is assessed .Which amino acid will have the lowest concentration? • A. Lysine • B.methionine • C.Glycine • D.proline • E.Cysteine

  37. Elastinfibres in the alveolar walls of the lungs can be stretched easily during inspiration and recoil to their original shape once the force is released. This process facilitates expiration. The property described can be best explained by: • Heavy posttranslational hydroxylation • High content of polar amino acids • Chain assembly to form a triple helix • Interchaincrosslinks involving lysine • Abundant interchain disulfide bridges

  38. 3. A 14-year old male presents to your office complaining of easy bruising. Physical examination reveals soft and loose skin as well as multiple ecchymoses in the forearm and pretibial regions. Histologic evaluation with electron microscopy shows collagen fibrils that are abnormally thin and irregular. Which of the following stages of collagen synthesis is most likely impaired in this patient? • RNA signal sequence recognition • Amino acid incorporation into polypeptide chain • Triple helix formation • Lysine residue hydroxylation • cleavage of propeptides

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