COLLAGEN

(STRUCTURE, FUNCTION AND ABNORMALITIES)

COLLAGEN
 most abundant fibrous protein in the animal

kingdom.
 major component of most connective tissue.  25 to 30 percent of the total protein in the

human body.
 comprises three polypeptide chains (a-chains)

which form a unique triple-helical structure.

 Types I, II and III are the most abundant and

form fibrils of similar structure.

 25 distinct types of collagen made up over 30

distinct polypeptide chains (different collagen genes ).

Functions:
 provides strength, support, integrity, and

structure.
 needed to repair tissue defect and to restore

structure and function.

 Major determinant of one s appearance

(Amount and Quality)

4 Common types of Collagen:

 Type I Collagen
-forms a triple helix composed of three chains or strands -1050 amino acids and approximately 300 nanometers long -extremely strong (its strength per unit mass is greater than steel ) -forms the primary component of tendons, connective tissue structures that link muscles and bones. Collagen type I also helps reinforce your bones.

 Type II Collagen
-forms the primary component of cartilaginous tissue found in nose, ears and many joints in your body. - smaller than collagen type I fibrils and assume random orientations in a gelatinous matrix of protein-carbohydrate complexes, where they cross-link with collagen type IX. -associated with proteoglycans or "ground substance" and therefore functions as a shock absorber in our joints and vertebrae.

 Type III Collagen

-found in our skin as well as in blood vessels and internal organs. -often with Type I collagen, arranged in loose network. -adult, the skin contains about 80-percent Type I and 20-percent Type III collagen. In newborns, the Type III content is greater than that found in the adult. -During the initial period of wound healing, there is an increased expression of Type III collagen.

 Type IV Collagen
-found in basement membranes and basal lamina structures and functions as a filtration system. -has a complex interactions in noncollagenous components of the basement membrane, a meshwork is formed that filters cells as well as molecules and light ex. 1. lens capsule of the eye, the basement membrane plays a role in light filtration 2. In the kidney, the glomerulus basement membrane is responsible for filtration of the blood to remove waste products. 3. In the walls of blood vessels, basement membrane controls the movement of oxygen and nutrients out of the circulation and into the tissues.

 Type V Collagen

-found in essentially all tissues and is associated with Types I and III.
-often found around the perimeter of many cells and functions as a cytoskeleton (particularly abundance in the intestine). -cells surfaces, hair and placenta.

Other Type of Collagen:

Type I II III IV V VI VII VIII IX X XI Notes
present in scar tissue, the end product when tissue heals by rskin, artery walls, the endomysium of myofibrils, fibrocartilage, and the organic part of bones and teethepair. It is found in tendons, Hyaline cartilage, makes up 50% of all cartilage protein. Vitreous humour of the eye. produced quickly by young fibroblasts before the tougher type I collagen is synthesized. Reticular fiber. Also found in artery walls, skin, intestines and the uterus basal lamina; eye lens. Also serves as part of the filtration system in capillaries and the glomeruli of nephron in the kidney. most interstitial tissue, assoc. with type I, associated with placenta most interstitial tissue, assoc. with type I

Gene Code
COL1A1, COL1A2

Disorder
osteogenesis imperfecta, EhlersDanlos Syndrome, Infantile cortical hyperostosis aka Caffey's disease Collagenopathy, types II and XI Ehlers-Danlos Syndrome, Dupuytren's contracture Alport syndrome, Goodpasture's syndrome Ehlers-Danlos syndrome Ulrich myopathy and Bethlem myopathy epidermolysis bullosa dystrophica Posterior polymorphous corneal dystrophy 2 - EDM2 and EDM3 Schmid metaphyseal dysplasia Collagenopathy, types II and XI

COL2A1 COL3A1

COL4A1, COL4A2, COL4A3, COL4A4, COL4A5, COL4A6 COL5A1, COL5A2, COL5A3 COL6A2, COL6A3 COL7A1 COL8A1, COL8A2 COL9A1, COL9A2, COL9A3 COL10A1 COL11A1, COL11A2

forms anchoring fibrils in dermal epidermal junctions some endothelial cells FACIT collagen, cartilage, assoc. with type II and XI fibrils hypertrophic and mineralizing cartilage cartilage

Type XII XIII XVII XXIX

Notes
FACIT collagen, interacts with type I containing fibrils, decorin and glycosaminoglycans integrin a1b1, fibronectin and components of basement membranes like nidogen and perlecan. transmembrane collagen, also known as BP180, a 180 kDa protein epidermal collagen

Gene Code
COL12A1

Disorder

COL13A1

COL17A1

Bullous pemphigoid and certain forms of junctional epidermolysis bullosa Atopic dermatitis

COL29A1

General stage of Collagen Synthesis:

 mRNA synthesis  protein synthesis  post-translational modifications  degradation

Structure of Collagen:
 With unusual amino acid composition  Glycine, Proline and Hydroxyproline are arranged in repetitious tripeptide seqeunce.

Gly-X-Y X- any Amino Acid or frequenly Proline Y- Hydroxyproline or Hydroxylysine

 Glycine (Gly) is found at almost every third residue  Proline (Pro) makes up about 17% of collagen

Inside the cell (Intracellular)

1. mRNA Processing -mRNA for each collagen type is transcribed from the gene (DNA blueprint) 2. Translation -2 peptide Chain is produced: Alpha-1 and Alpha-2 chain (preprocollagen) * registration peptides * signal peptide

- found in membranous-bound ribosomes(rER) - Polypeptide chains are released into the lumen of the RER -Signal peptides are cleaved inside the RER (central protein systhesis)and the chains are now known as pro-alpha chains.
3. Hydroxylation

Proline & Lysine (HYROXYLASES) formed: Hydroxyproline Hydroxylysine -which need cofactor to secure the integrity of helical structure.

4. Glycosylation -Galactose and Glucose -Catalyzed by Galactosyl & Glucosyl traferases

* Triple helical structure is formed inside the endoplasmic reticulum from each two alpha-1 chains and one alpha-2 chain.

Procollagen (larger precursor molecules) is shipped to the golgi apparatus, where it is packaged and secreted by exocytosis.

Out side the Cell(Extracellar)

Registration peptides are cleaved and tropocollagen is formed by procollagen protienases. Cross-link formation -Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking (aldol reaction) by lysyl oxidase which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers Collagen may be attached to cell membranes via several types of protein, including fibronectin and integrin.

 

Primary structure of a protein is the sequence of amino acids. Secondary protein structure occurs when the sequence of amino acids are linked by hydrogen bonds. This level of structure takes the form of either a pleated sheet or a helix. Tertiary structure describes the folding and other contortions of a polypeptide chain that result from the molecular interactions among the R groups of the different amino acids. The arrangement of two or more polypeptide chains in a protein make up its quaternary structure

Vit.C in Collagen formation and Functions:

 Proline and Lysine residues

-Hydroxyproline and Hydroxylysine by Prolyl hydroxylase & Lysly hydroxylase Vit.C - essential for proper structural allingment. -development, replacement and maintenance connective tissue, blood vessel and cartilage.

Collagen in wound repair

 Wound repair - a complex and dynamic process of restoring cellular structures and tissue layers
 Hemostasis - platelets  Inflammation neutrophils, macrophage, metalloproteinase  Granulation - tissue granulation and vascularisation; fibroblasts lay down new collagen and other proteins; ECF is now functional  Remodeling fibroblasts will remodel and link the collagen fibers
Collagen structural support; cleavage products from collagen degradation stimulates fibroblast and vascular endothelial cells proliferation

Collagen in wound repair

Hemostasis
 Platelets aggregate around exposed collagen

release of factors strengthens aggregate = platelet plug

 Release of cytokines inflammatory cells

(neutrophils, macrophage, eosinophils)

Inflammatory
 Activated macrophage increase in inflammatory cytokines migration of fibroblasts, epithelial cells, and vascular endothelial cells into the wound = cellularity of the wound increases

Proliferation
 Cleavage products resulting from collagen degradation stimulate fibroblast proliferation Metalloproteinase degrades the nonviable collagen  Stimulation of vascular endothelial cell proliferation = Angiogenesis

 Tissue inhibitors = decrease in

metalloproteinase = increase collagen deposition of fibroblast  New collagen + blood supply = functional ECM granulation  Keratinocytes migrate to newly formed granulation tissue = reepithelialization

Remodeling Phase
 Angiogenesis ceases  Fibroblasts will

remodel and cross link the collagen fibers = stronger scar

Collagen and Aging

 The increasingly brittle and rigid character of aging connective tissue results from accumulated covalent cross-links.  Heat disruption of forces shortening

Collagen and Aging

 Increase in collagenase

underexpression of inhibitors conversion of fibroblast to fibroclast degradation of ECF

DISEASES AND GENETIC DISORDERS

Osteogenesis Imperfecta
 Hereditary disease of the

bones and connective tissue due to mutation of gene encoding in Type I collagen
 Hypermobility of joints  Fragile bones  Poor teeth  Growth retardation  Blue sclera

Ehlers-Danlos Syndrome
 a group of more than 10 different inherited disorders; all involve a genetic defect in collagen and connective tissue synthesis and structure.  can affect the skin, joints, and blood vessels

Ehlers-Danlos Syndrome
 Hyperextensibility of the

skin  Abnormal tissue fragility  Increased joint mobility  Ehlers Danlos syndrome type IV is associated with rupture of arteries or the bowel, with possible lifethreatening consequences

Alport Syndrome
 heterogeneous genetic  Hearing loss  Hematuria  May develop end stage

disorders affecting the structure of type IV collagen, a major component of basement membranes (renal glomeruli).

renal disease

Dystrophic Epidermolysis Bullosa

 a group of inherited

bullous disorders characterized by blistering lesions on the skin and mucus production areas

Basement membrane zone

Dystrophic Epidermolysis Bullosa

 caused by defects of anchoring fibrils (Type VII collagen)  Blisters most commonly appear at sites of friction and minor trauma such as the feet and hands  may also occur on internal organs, such as the esophagus, stomach and respiratory tract, without any apparent friction

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