Collagen Objectives 122345- Structure of collagen Distribution of collagen Functions of collagen Biosynthesis of collagen Degeneration of collagen Diseases of collagen (Clinical Applications)

What is collagen ? Collagen is the most abundant protein in the human body. Collagen is a fibrous protein

Collagen serves as having structural functions in the body . Collagen is found in components of - Skin - Connective tissue - Blood vessel walls

- Sclera & cornea of the eye General structure of collagen Collagen protein has primary & secondary levels of structure. A typical collagen molecule is a long, rigid structure in which three polypeptides (a chains) are wound around one another in a rope-like triple helix. Types and organization of collagen molecules

are governed by the structural role collagen plays in a particular organ. in some tissues, collagen is dispersed as a gel as in the vitreous humor of the eye. in other tissues, collagen may be arranged in parallel fibres that provide great strength as in tendons in cornea of eye, collagen is stacked so as to transmit light. Types of collagen Collagen super family of proteins includes more than 20 collagen types The three polypeptide a chains are held together by hydrogen bonds between chains a chains are ~1000 amino acids long but with slightly different properties

These a chains are combined to form the various types of collagen found in tissues. Examples: Type 1 collagen: Most common collagen contains two a1 chains and one a2 chain a12 a2 Type II collagen: contains three a1 a13 most abundant types of collagen

Detailed structure of collagen 1- Amino acid sequence Collagen is rich in proline & glycine Proline : by its ring structure facilitates the formation of the helical conformation of each a chain. Glycine (smallest amino acid): present in every third position of the chain. It fits into the spaces where the three chains of the helix come together. Glycines are parts of a repeated sequence [-Gly- X Y ] where: X is frequently Proline Pro & Y is often Hydroxyproline Hyp (can be Hydroxylsine Hyl)

So, most of the a chain can be POLYTIPEPTIDE with sequence of: (- Gly- Pro Hyp -) 333 Detailed structure of collagen (cont.) 2-Triple-helical structure Collagen as a fibrous protein has an elongated , triple-shaped helical structure in which side chains (R- groups) of its amino acid are on the surface of the triple-helical molecule.

This allows bond formation between the exposed R-groups of neighbouring collagen monomers resulting in their aggregation into long fibres. Detailed structure of collagen (cont.) 3- hydroxyproline & hydroxylysine Hydroxyproline & hydroxylysine are not present in most proteins, however, collagen contains them.

These two amino acids result from the hydroxylation of some proline & lysine amino acids after their incorporation into poly peptide chains during protein biosynthesis. (i.e. post-translational modification) Hydroxyproline is important in stabilizing the triple-helical structure of collagen because it increases (maximises) interchain hydrogen bond formation. Detailed structure of collagen

Proline is hydroxylated by prolyl hydroxylase enzyme which requires ascorbic acid (vitamin C) as a coenzyme (cont.) Detailed structure of collagen

(cont.) 4- glycosylation The hydoxyl group of hydroxlysine amino acids of collagen may be glycosylated by enzymatic reaction. Glucose & galactose molecules are attached to the polypeptide chain prior to triple helix formation.

Biosynthesis of collagen The polypeptide precursors of collagen molecules are formed intracellularly in fibroblasts (or in osteoblasts of bone & chondroblasts of cartilage) & then secreted into the extracellular matrix. In the extracellular matrix, mature collagen monomers are formed.

Collagen monomers aggregate & become cross-linked to form collagen fibrils. Biosynthesis of collagen (cont.) intracellular stage (in fibroblasts) 1- Formation of pro-a chain (protein biosynthesis on ribosomes of RER) 2- Hydroxylation of some proline & lysine amino acids on Y-position

of Gly X Y sequence of pro-a chain by enzymes prolyl & lysyl hydroxylases (requires vitamin C) In cases of vitamin C deficiency (Scurvy): Hydoxylation of proline & lysine will not occur, with no cross linking resulting in decrease in the tensile strength of collagen fibers. Clinical manifestations: bruises in the limbs due to subcutaneous extravasation of blood (capillary fragility) 3- Glycosylation: some hydroxylysine amino acids are glycosylated by glucose or glucose-galactose 4- Assembly & Secretion; Pro-a collagen form procollagen which is a precursor of collagen that has a central region of triple helix, flanked by non-helical amino and caboxy- terminal extensions of the pro-a chain. Procollagen molecules are translocated to the Golgi apparatus where they are packaged in the secretory

vesicles which fuse with cell membrane causing the release of procollagen into extracellular space. Intracellular Stage of Collagen Synthesis (in fibroblasts) Bruises in lower limb in a case of scurvy Biosynthesis of collagen (cont.)

Extracellular Stage (in matrix) 5- Extracellular cleavage of procollagen molecules: Procollagen molecules are cleaved by N- & C- procollagen peptidases which remove the terminal nonhelical peptides resulting in the formation of triple helical tropocollagen molecules. 6- Formation of collagen fibrils: Individual tropocollagen molecules associate to form a collagen fibril. Collagen fibril form an ordered, overlapping, parallel array with adjacent collagen molecules in a staggered pattern. 7- Cross-link formation of collagen fibrils

by the enzyme lysyl oxidase which oxidatively demainates some lysine and hydroxylysine amino acids in collagen forming aldhydes. An aldehyde from one collagen polypeptide link with lysine or hydroxylysine amino acids of a neighboring collagen polypeptide to form covalent cross-links resulting in mature collagen formation. Procollagen Tropocollagen (Collagen molecule)

Collagen Fibril Extracellular Stage of Collagen Synthesis (in matrix) Collagen Molecule Collagen Fibril

Cross-links formation in collagen NH2 of lysine on neighbor collagen polypeptide Aldhyde group formed

on one collagen polypeptide Cross-link between adjacent collagen polypeptides Degradation of collagen Half-lives of normal collagen are several years.

Collagen fibrils is degraded by collagenases (matrix metalloproteinases) that cleave a collagen molecule into two fragments 3/4 & length. Then by other matrix proteases, these fragments are degraded to individual amino acids.

Collagen diseases Defects in any one of the steps of collagen fibre synthesis can result in a genetic disease involving inability of collagen to form fibres properly (& thus collagen will not provide tissues with the needed tensile strength). More than 1000 mutations have be identified in 22 genes coding for 12 of the collagen types. Collagen Diseases

(cont.) Ethlers-Danlos syndrome (EDS) Results from inherited defects in the metabolism of fibrillar collagen molecules. EDS can result from: Deficiency in collagen-processing enzymes as lysyl hydroxylase deficiency or procollagen peptidase deficiency Mutations in the amino acid sequences of collagen type I, II, III, or type V.

(most important mutations are in of genes for type III) Collagen containing mutant chains is not secreted. So, it is degraded or accumulated in cells. Clinical Manifestations: Lethal vascular problems of arteries (Collagen III is an important component of arteries) Fragile & stretchy skin Loose joints Collagen diseases (cont.)

Osteogenesis imperfecta (OI) (Brittle bone syndrome) Bones easily bend & fracture Retarded wound healing Rotated & twisted spine leading to humped-back appearance

Recently Viewed Presentations

  • Datenverarbeitung Teil 1 - THM

    Datenverarbeitung Teil 1 - THM

    Dieses Unterkapitel wird die Wurzel in der Menschheitsgeschichte und auch die Entwicklung des Rechners vorstellen. Inhalt Information in der Geschichte Automaten und Steuerungen Erleichterung der Rechenarbeit Pioniere der Informatik - Praktiker Pioniere der Informatik - Theoretiker Die ...
  • Grande Guerra

    Grande Guerra

    Title: GRANDE GUERRA Author: Ada Last modified by: rebecca regli Created Date: 4/21/2008 10:23:17 PM Document presentation format: Presentazione su schermo
  • Follow the Rainbow - University of West Georgia

    Follow the Rainbow - University of West Georgia

    Jordan likes to play. She plays inside. She plays outside. One day she saw a rainbow. "Let's see where the rainbow goes." The End! Does it go to Grandma's house? Does it go to ? Does it go to a...
  • Reconnecting to the Heart of Kiwanis Rocky Mountain

    Reconnecting to the Heart of Kiwanis Rocky Mountain

    It is designed to encourage Kiwanians to move forward with a vision toward the future. Through our projects built around the themes of fun, service, action, inclusion and relationships, we will engage in our communities and the world, increasing the...
  • Welcome to The Physics Project

    Welcome to The Physics Project

    welcome to the physics project electro magnetic induction objectives : it enables the students to a ) develop scientific interest b) acquire more knowledge about electro magnetic induction c) develop practical skill electricity !
  • Hammett plots in the world of enzymes

    Hammett plots in the world of enzymes

    Hammett plots in the world of enzymes. Erika Aoyama and Megan Browning. Figure 1: A Hammett plot from Louis Hammett's original 1935 paper in which he described Hammett plots. Reference: Hammett, L. P. Chem. Rev. 1935, 17 (1), 125-136. O....
  • New Teacher Curriculum Day - Math Session

    New Teacher Curriculum Day - Math Session

    Math workshop has moved away from Stations and now looks more like Reader's/Writer's Workshop. These three books have valuable information in them regarding working with students in small groups, one-on-one, as well as whole group and how to encourage more...
  • Psychology of Color

    Psychology of Color

    Color is crucial! Most important and impactful element. First thing people notice when they enter a room. Helps create mood. Leaves a lasting impression. Easiest way to remodel, upgrade, or transform a room. Easiest way to make an impression with...