Collagen! - The connective Tissue Protein

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This was a seminar I had done for my Biochemistry class while studying naturopathy and yoga -BNYS (1st Year). enjoy.

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Collagen! - The connective Tissue Protein

  1. 1. Collagen The connective tissue protein
  2. 2. Why study tissue proteins?  To understand normal body functions .  In development  In inflammatory states  Aging process.  To identify the cause of various genetic and metabolic disorders related to tissue proteins  In the spread of cancer cells.  Several diseases (eg:Osteogenesis imperfecta and a number of types of the Ehlers-Danlos syndrome) are due to genetic disturbances of the synthesis of collagen.  Components of proteoglycans are affected in the group of genetic disorders known as the mucopolysaccharidoses.  To use and apply them in the medical, industrial, commercial fields.  In food products, cosmetic surgery.  The gelatin used in food and industry is derived from the partial hydrolysis of collagen.
  3. 3. The Extracellular Matrix  The space outside the cells of a tissue is filled with a composite material called extracellular matrix(ECM).  This ECM is also known as the connective tissue. It is composed of - a) Gel with interstitial fluid. b) 3 major classes of biomolecules:  Structural proteins: collagen, elastin and Keratin(epidermal tissues)  Specialized proteins: e.g. fibrillin, fibronectin, and laminin.  Proteoglycans(Mucoproteins) : Conjugated proteins consisting of  Protein + Carbohydrate(5%-95%)  Carbohydrate part is in the form of Glycosaminoglycans [GAGs].  Thus, the extracellular matrix (ECM) is a complex structural entity surrounding and supporting cells that are found within mammalian tissues.
  4. 4. The Extra cellular matrix
  5. 5. Collagen  Most abundant insoluble fibrous protein in the connective tissue of mammals.  Makes up about 25% to 35% of the whole-body protein content.  Scleroprotein secreted from the cells called fibroblasts.  In greek ‘kolla’ means ‘glue’.Collagen is also called as glue-producer.  Distribution of collagen varies in different tissues.  Also found in mucous membranes, nerves,Blood vessels, and organs. 90% 85% 70% 4% bones tendons skin liver Collagen fibers in muscle tendons
  6. 6. Functions Of Collagen  It imparts strength, support, shape and elasicity to the tissues.  It accounts for 6% of the weight of strong, tendinous muscles  It provides flexibility, support, and movement to cartilage.  It encases and protects delicate organs like kidneys and spleen.  It fills the sclera of the eye in crystalline form.  Teeth(dentin) are made by adding mineral crystals to collagen.  Collagen contributes to proper alignment of cells for cell proliferation and differentiation.  When exposed in damaged blood vessels, it initiates thrombus formation
  7. 7. Types Of Collagen  In humans, there are at least 19 distinct types of collagen made up of 30 distinct polypeptide chains (each encoded by a separate gene).  They are subdivided into a number of classes based primarily on the structures they form  However, 90% of the collagen in the body are of type I, II, III, and IV.  These types determine the physical properties of specific tissues and perform their specialized function.
  8. 8. Structure Of Collagen The basic structural unit of a collagen molecule is a triple helix. Triple helical structure may occur throughout the molecule or only in a part of it. Structure Of type I mature Collagen:  Triple helical structure occurs throughout the molecule.  This triple helix is composed of 3 polypeptide chains twisted around each other.  Each polypeptide/alpha chain is in turn a left handed helix with 3 amino acids per turn totally containing approximately 1000 amino acids per chain. Alpha chain Triple Helix Amino- acids
  9. 9. Each alpha chain has an unusual abundance of 3 amino-acids glycine, proline and hydroxyproline.  Glycine occurs at every third position in the amino acid sequence which can be represented as (Gly-X- Y)n.  X and Y are other amino acids of which proline and hydroxyproline occupy 100 positions each.  Glycine occupies the crowded center of the triple helix as it has a small side chain[ H atom] where as Hydroxyproline and proline point outwards imparting rigidity to the triple helix.  The alpha chains are wound around each other in a right handed super helix to form a rod like molecule 1.4nm wide and 300nm long [Gly-X-Y]n
  10. 10. The triple helices are stabilized by Hydrogen bonds, covalent cross- links, electrostatic and hydrophobic interactions and van der waals forces. The covalent cross links within and between the helices are formed by copper dependent enzyme lysyl oxidase between the lysine and hydroxylysine residues. These triple helical molecules pack together side by side to form elongated fibrils. Fibrils are displaced longitudinally from each other by 67 nm [one quatter of its length] to form a quarter staggered arrangement. Fibrils bundle up to form fibers making up tissues. Cross link formation
  11. 11. Structure of collagen fibers
  12. 12. Biosynthesis of Collagen  Collagen synthesis occurs in the fibroblasts, osteoblasts in bone, chondroblasts in cartilage and odontoblasts in teeth.  First synthesized in precursor form of preprocollagen polypeptide chain in the ribosomes during translation  The leader sequence of amino acids[signal peptide] in the preprocollagen directs it to enter the lumen of E.R  In the lumen of E.R, the Signal peptide is cleaved to form procollagen.  The proline and lysine amino acids in the procollagen chain undergo hydroxylation and glycosylation known as post translational modifications.  Disulfide bonds are formed between three procollagen chains which twist around each other to form a triple helix molecule.This step is called registration.  This Procollagen molecule is secreted into the extracellular matrix from the golgi compartment of the E.R.  Here, the procollagen aminoproteinase and carboxy proteinase enzymes remove extra terminal amino acids from the procollagen molecule to form collagen .  The collagen molecules assemble into fibrils and inturn fibers being stabilized by the covalent cross-links.
  13. 13. Biosynthesis of collagen from Preprocollagen
  14. 14. Synthesis Of Collagen
  15. 15. Abnormalities associated with collagen  Collagen-related diseases arise from  genetic defects  nutritional deficiencies  They affect the biosynthesis, assembly, postranslational modification, secretion, or other processes involved in normal collagen production.  These include :  Ehler Danlos syndrome  Alport syndrome  Epidermolysis bullosa  Osteogenesis Imperfecta  Chondrodysplasias [affects cartilage]  Scurvy  Osteolathyrism
  16. 16. Ehler Danlos Syndrome  Ehlers-Danlos Syndrome is a group of inherited connective tissue disorders.  CAUSE  abnormalities in the synthesis and metabolism of collagen  Mutations in the collagen genes: COL1A1, COL1A2, COL3A1, COL5A1, COL5A2  a deficiency of enzyme lysyl hydroxylase.  A deficiency of procollagenN-proteinase, causing formation of abnormal thin, irregular collagen fibrils  EFFECT  Mutations alter the structure, production, or processing of collagen or proteins that interact with collagen  WeakenS connective tissue in the skin, bones, blood vessels, and organs causing-  Skin hyperextensibility  Joint dislocations  Tissue fragility  Poor wound healing.
  17. 17. Ehler-Danlos Syndrome •Hyperextensibility of skin •Hypermobility of joints
  18. 18. Alport Syndrome  Alport syndrome is a genetic disorder characterized by glomerulonephritis, endstage kidney disease, and hearing loss.  It also affects the eyes.  The presence of blood in the urine[hematuria] is almost always found in this condition.  CAUSE  Mutations in COL4A3,COL4A4,COL4A5 collagen biosynthesis genes.  These prevent the production or assembly of the type IV collagen network in the basement membranes.  kidneys are scarred and unable to filter waste products resulting in hematuria and renal disease. Alport syndrome affecting eyes
  19. 19. Epidermolysis Bullosa • Epidermolysis bullosa refers to a group of inherited disorders that involve the formation of blisters following trivial trauma. • CAUSE  mutations in COL7A1, affecting the structure of type VII collagen.  Type VII collagen forms delicate fibrils that anchor the basal lamina to collagen fibrils in the dermis.  These anchoring fibrils are reduced in this form of the disease, causing friction and blistering. • EFFECT  Blistering and painful sores like third degree burns Blister formation
  20. 20. Osteogenesis Imperfecta  Osteogenesis imperfecta or Brittle Bone Disease is a genetic bone disorder due to decrease dcollagen formation.  CAUSE  Mutations in the COL1A1 andCOL1A2 genes coding for procollagen chains.  Replacement of glycine by another bulkier amino acid resulting in decreased collagen or improper procollagen structure forming abnormal fibers.  Mutations also cause ‘procollagen suicide ‘  All these cause brittleness.  EFFECT  Thin,t ransclucent, blue scleras.  Affected infants may be born with multiple fractures and not survive.  weak muscles, brittle teeth, a curved spine and hearing loss.
  21. 21. Chondrodysplasias  Chondrodysplasias are a mixed group of hereditary disorders affecting cartilage.  One example is Stickler syndrome, manifested by degeneration of joint cartilage and of the vitreous body of the eye.  CAUSE  Mutations in the COL2A1 gene, leading to abnormal forms of type II collagen.  EFFECT  shortlimbed dwarfism  skeletal deformities.
  22. 22. Osteolathyrism  Osteolathyrism is a collagen cross-linking deficiency caused by dietary over- reliance on the seeds of Lathyrus sativus (kesari dal) in some parts of India.  CAUSE  Osteolathyrogenic compounds like Beta- aminopropionitrile(BAPN) and Beta- oxalyl aminoalanine [BOAA] found in Kesari dhal inhibit enzyme lysyl oxidase required for the formation of cross links in the triple helices  EFFECT  weakness and fragility of skin, bones, and blood vessels  Paralysis of the lower extremities associated with neurolathyrism
  23. 23. Scurvy  Scurvy is a disease due to deficiency of vitamin C  It is not a genetic disease.  It is related to improper collagen formation  CAUSE  Vitamin C [ascorbic acid ]is required as a cofactor for hydroxylase enzymes during the hydroxylation of proline and lysine in the synthesis of collagen.  Deficiency causes impaired collagen synthesis due to deficiency of hydroxylases.  EFFECT  Bleeding of gums  Poor wound healing  Subcutaneous hemorrhages
  24. 24. Uses Of Collagen  Industrial Uses  Collagen is used as temporary thermoplastic glues in musical instruments like violin and guitar .  Recently used as a fertilizer  Gelatin derived from the partial hydrolysis of collagen is used in food products like desserts, jellies.  It is also used in pharmaceutical, cosmetic, and photography industries.  Medical uses  Mild benefit to rheumatoid arthritis patients.  Keeps the valvular leaflets of heart in shape.  Helps in the deposition of calcium during aging.  Used in cosmetic surgery, for burn patients for reconstruction of bone and a wide variety of dental, orthopedic and surgical purposes.  Main ingredient of cosmetic makeup.  Human collagen is used for immunosuppression during transplantation.

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