Presentation on theme: "Dr.S.Chakravarty MBBS, MD. Describe the structure and formation of collagen and elastin List the various steps in Post translational modification."— Presentation transcript:
Dr.S.Chakravarty MBBS, MD
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 2
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. 4
Alpha helical secondary structure. Low water solubility A long narrow rod like structure. Role in determining cellular structure and function. 5
Dispersed as a gel – Vitreous humor Tight parallel fibres – Tendons Stacked for minimal scattering – Cornea Mechanical shearing – Bone. 7
Fibril formingTissueFunction Type 1 (90%) Tendon, bone, ligaments and skinResistance to tension Type 2Hyaline and elastic cartilageResistance to pressure Type 3Skin, muscle, blood vesselsStructural framework for expanding tissues Network forming TissueFunction Type 4Basement membraneFiltration and support Anchoring fibrilsTissueFunction Type 7EpitheliumAnchors basal cells to underlying stroma 8 Type I collagen is stronger than steel !!
1. Molecular collagen (pre pro collagen and pro collagen) – soluble 2. Microfibrils – tropocollagen ( insoluble) 3. Fibrils 4. Fibres 10
Left handed helix 3 such strands wound together Usmle!
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 3 rd residue is glycine. The repetitive a.a sequences can be denoted by Gly-X-Y, where X and Y are commonly Proline and Hydroxyproline.
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.
Quarter staggered Arrangement The trophocollagen molecules are arranged in in such a way that each row moves ¼ length over last row and the 5 th 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
19 USMLE concept!
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. 20
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 21 (from Kadler, 1996)
22 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 antiresorptive osteoporosis 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.
Cu 2+ / vitamin B 6 USMLE concept !
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) 24
Covalent X-links between Allysine and hydroxylysine Tropocollagen molecule triple helix of -chains.
27 Molecular Cell Biology, 4th edition Harvey Lodish, Arnold Berk, S Lawrence Zipursky, Paul Matsudaira, David Baltimore, and James Darnell.
28 Kaplan USMLE step 1 lecture notes
Helps in retaining the shape after stretching. Connective tissue protein. lungs, large blood vessels, elastic ligaments 29
Outer cover - Microfibrils containing fibrillin 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) 30
3D network of cross-linked polypeptides – (tropo elastin) cross links involve Lys and alLys –lysyl oxidase 4 Lys can be cross-linked into desmosine Desmosines account for elastic properties Elastin Desmosine
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
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 USMLE concept !
Table 48–5. Major Differences Between Collagen and Elastin CollagenEl as tin 1. Many different genetic typesO ne ge ne tic ty pe 2. Triple helixN o tri pl e he lix ; ra nd o m co il co nf or m ati on s pe r mi tti ng str et ch in g 3. (Gly-X-Y) n repeating structure N o (G ly- X- Y) n re pe ati ng str uc tu re 4. Presence of hydroxylysineN o hy dr ox yl ysi ne 5. Carbohydrate-containingN o ca rb oh yd ra te 6. Intramolecular aldol cross-linksIn tr a m ol ec ul ar de s m os in e cr os s- lin ks 7. Presence of extension peptides during biosynthesisN o ex te ns io n pe pti de s pr es en t du ri ng bi os yn th es is Major Differences Between Collagen and Elastin Collagen Elastin 1.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. Intramolecular aldol cross-links Intramolecular desmosine cross-links 7. Presence of extension peptides No extension peptides present during biosynthesis during biosynthesis
Serine type elastase: neutrophils, macrophages, fibrblasts. Matrix metalloproteinases – mmp-12 and 7, gelatinases. 35
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). 8 2 nm
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
The structure of keratin is strengthened by disulfide cross- links from one helix to another. 10
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 42
1. Elastin fibres 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: a) Heavy posttranslational hydroxylation b) High content of polar amino acids c) Chain assembly to form a triple helix d) Interchain crosslinks involving lysine e) Abundant interchain disulfide bridges 43
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? a) RNA signal sequence recognition b) Amino acid incorporation into polypeptide chain c) Triple helix formation d) Lysine residue hydroxylation e) cleavage of propeptides 44