collagen report structure, function and abnormalities)(1)

8/6/2019 Collagen Report Structure, Function and Abnormalities)(1)

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(STRUCTURE, FUNCTION ANDABNORMALITIES)

COLLAGEN


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COLLAGEN

most abundant fibrous protein in the animalkingdom.

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.


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Types I, II and III are the most abundant and

form fibrils of similar structure.

25 distinct types of collagen made up over 30distinct polypeptide chains (different collagen

genes ).


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Functions:

provides strength, support, integrity, and

structure.

needed to repair tissue defect and to restore

structure and function.

Major determinant of ones appearance

(Amount and Quality)


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4 CommontypesofCollagen:

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 oftendons, connective tissuestructures that link muscles and bones. Collagen type I also helps

reinforce your bones.


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Type II Collagen

-forms the primary component ofcartilaginous tissue found in

nose, ears and many joints in your body.

- smaller than collagen type I fibrils and assume randomorientations in a gelatinous matrix of protein-carbohydratecomplexes, where they cross-link with collagen type IX.

-associated with proteoglycans or "ground substance" andtherefore functions as a shock absorber in our joints and vertebrae.


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Type III Collagen-found in our skin as well as in blood vessels and internal organs.

-often withType I collagen, arranged in loose network.

-adult, the skin contains about 80-percentType I and 20-percentType III collagen. In newborns, theType III content is greater thanthat found in the adult.

-During the initial period of wound healing, there is an increasedexpression ofType III collagen.


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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 thebasement membrane, a meshwork is formed that filters cells as wellas molecules and light

ex.

1. lens capsule of the eye, the basement membrane plays a rolein light filtration

2. In the kidney, the glomerulus basement membrane isresponsible for filtration of the blood to remove waste products.

3. In the walls of blood vessels, basement membrane controlsthe movement of oxygen and nutrients out of the circulation and

into the tissues.


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Type V Collagen-found in essentially all tissues and is associated withTypes 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.


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Other TypeofCollagen:

Type Notes Gene Code Disorder

I present in scar tissue, the end product when tissue healsby rskin, artery walls, the endomysium of myofibrils,fibrocartilage, and the organic part of bones andteethepair. It is found in tendons,

COL1A1, COL1A2 osteogenesis imperfecta, Ehlers-Danlos Syndrome, Infantile

cortical hyperostosis aka Caffey'sdisease

IIHyaline cartilage, makes up 50% ofall cartilage protein.

Vitreous humour oftheeye.

COL2A1 Collagenopathy, types II and XI

III produced quickly by young fibroblasts before thetougher type I collagen is synthesized. Reticular fiber.Also found in artery walls, skin, intestines and the uterus

COL3A1Ehlers-Danlos Syndrome,

Dupuytren's contracture

IV basal lamina; eye lens. Also serves as part of thefiltration system in capillaries and the glomeruli ofnephron in the kidney.

COL4A1, COL4A2, COL4A3,

COL4A4, COL4A5, COL4A6

Alport syndrome, Goodpasture'ssyndrome

V most interstitial tissue, assoc. with type I, associatedwith placentaCOL5A1, COL5A2, COL5A3 Ehlers-Danlos syndrome

VI most interstitial tissue, assoc. with type I COL6A2, COL6A3 Ulrich myopathy and Bethlemmyopathy

VII formsanchoring fibrils indermal epidermal junctions COL7A1 epidermolysis bullosadystrophica

VIII someendothelial cells COL8A1, COL8A2 Posteriorpolymorphous cornealdystrophy 2

IX FACIT collagen, cartilage, assoc. with type II and XIfibrilsCOL9A1, COL9A2, COL9A3 - EDM2 and EDM3

X hypertrophic and mineralizing cartilage COL10A1 Schmid metaphyseal dysplasia

XI cartilage COL11A1, COL11A2 Collagenopathy, types II and XI


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Type Notes Gene Code Disorder

XII FACIT collagen, interacts withtype I containing fibrils, decorinand glycosaminoglycans

COL12A1

XIII integrin a1b1, fibronectin andcomponents of basementmembranes like nidogen andperlecan.

COL13A1

XVII transmembranecollagen, alsoknown as BP180, a 180 kDaprotein

COL17A1 Bullouspemphigoid and certain

forms of junctional epidermolysis

bullosa

XXIX epidermal collagen COL29A1 Atopic dermatitis


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GeneralstageofCollagen

Synthesis:

mRNA synthesis

protein synthesis

post-translational modifications

degradation


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StructureofCollagen:

With unusual amino acid composition

Glycine, Proline and Hydroxyproline are arranged inrepetitious 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


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Insidethecell (Intracellular)

1. mRNA Processing

-mRNA for eachcollagen type is

transcribed fromthe gene (DNA

blueprint)

2. Translation

-2 peptide Chain is

produced:

Alpha-1 and Alpha-2

chain(preprocollagen)

* registration peptides

* signal peptide


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- found in membranous-bound

ribosomes(rER)

- Polypeptide chains are released

into the lumen of the RER

-Signal peptides are cleaved insidethe RER (central proteinsysthesis)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.


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4. Glycosylation

-Galactose and Glucose

-Catalyzed by

Galactosyl & Glucosyl traferases

* Triple helical structure is formed

inside the endoplasmic reticulumfrom each two alpha-1 chains and

one alpha-2 chain.

Procollagen (larger precursor

molecules) is shipped to the golgiapparatus, where it is packaged and

secreted by exocytosis.


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OutsidetheCell(Extracellar)

Registration peptides arecleaved and tropocollagen is

formed by procollagenprotienases.

Cross-link formation

-Multiple tropocollagen

molecules form collagen fibrils,via covalent cross-linking (aldol

reaction) by lysyl oxidase which

links hydroxylysine and lysineresidues. Multiple collagen fibrilsform into collagen fibers

Collagen may be attached to cellmembranes via several types of

protein, including fibronectin

and integrin.


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Primary structure of a protein is thesequence of amino acids.

Secondary protein structure occurs

when the sequence of amino acidsare 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 apolypeptide chain that result from

the molecular interactions amongthe R groups of the different amino

acids. The arrangement of two or more

polypeptide chains in a proteinmake up its quaternary structure


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Vit.C inCollagenformationand

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.


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Collagenin woundrepair

Wound repair - a complex and dynamic process ofrestoring cellular structures and tissue layers

Hemostasis - platelets

Inflammation neutrophils, macrophage, metalloproteinase

Granulation - tissue granulation and vascularisation; fibroblasts laydown 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 degradationstimulates fibroblast and vascular endothelial cells proliferation


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Collagenin woundrepair


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Hemostasis

Platelets aggregate around exposed collagen

release of factors strengthens aggregate =

platelet plug

Release of cytokines inflammatory cells

(neutrophils, macrophage, eosinophils)


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Inflammatory

Activated macrophage increase in inflammatory

cytokines migration of

fibroblasts, epithelial cells,and vascular endothelialcells into the wound =cellularity of the wound

increases


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Proliferation

Cleavage productsresulting from collagen

degradation stimulate

fibroblast proliferation Metalloproteinasedegrades the nonviablecollagen

Stimulation of vascularendothelial cellproliferation =

Angiogenesis


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Tissue inhibitors = decrease in

metalloproteinase = increase collagen

deposition of fibroblast New collagen + blood supply = functional

ECM granulation

Keratinocytes migrate to newly formedgranulation tissue = reepithelialization


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RemodelingPhase

Angiogenesis ceases

Fibroblasts will

remodel and cross link the collagen fibers= stronger scar


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CollagenandAging

The increasingly brittle and rigid character of agingconnective tissue results from accumulated covalentcross-links.

Heat disruption of forces shortening


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CollagenandAging

Increase in collagenase underexpression ofinhibitors conversionof fibroblast to

fibroclast degradation of ECF


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DISEASES AND GENETIC

DISORDERS


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Osteogenesis Imperfecta

Hereditary disease of thebones and connectivetissue due to mutation ofgene encoding inType I

collagen

Hypermobility of joints

Fragile bones

Poor teeth

Growth retardation

Blue sclera


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Ehlers-Danlos Syndrome

a group of more than 10different inherited

disorders; all involve a

genetic defect in collagenand connective tissuesynthesis and structure.

can affect the skin, joints,and blood vessels


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Ehlers-Danlos Syndrome

Hyperextensibility of theskin

Abnormal tissue fragility

Increased joint mobility

Ehlers Danlos syndrometype IV is associated with

rupture of arteries or thebowel, with possible life-threateningconsequences


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Alport Syndrome

heterogeneous geneticdisorders affecting thestructure of type IVcollagen, a majorcomponent ofbasement membranes(renal glomeruli).

Hearing loss

Hematuria

May develop end stagerenal disease


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DystrophicEpidermolysis Bullosa

a group of inheritedbullous disorderscharacterized byblistering lesions onthe skin and mucusproduction areas


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Basementmembrane zone


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DystrophicEpidermolysis Bullosa

caused by defects ofanchoring fibrils (Type VII

collagen)

Blisters most commonlyappear at sites of friction

and minor trauma such asthe feet and hands

may also occur on internalorgans, such as theesophagus, stomach andrespiratory tract, withoutany apparent friction


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Thank You!!

collagen report structure, function and abnormalities)(1)

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