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EXTRACELLULAR MATRIX(ECM)
Dr. Eman Khairy Lecturers of Medical biochemistry & Molecular Biology
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By the end of this topic you will be able to:
Recognize the importance of ECM and its component in the health and diseases. Describe the structural and functional properties of collagen and elastin, the major proteins in ECM. Describe the general properties of proteoglycans , fibronectin, and laminin.
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ECM contains 3 major classes of biomolecules
The space between cells that bind cells and tissue together ECM contains 3 major classes of biomolecules Fibrous (structural protein) Collagen Elastin Fibrillin Proteoglycan Chondrotin sulphate Dermatan sulphate Hyalouronic acid Adhesion proteins Fibronectin Laminin Integrin
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ADHESION MOLECULES Link component of matrix protein to each other and to cells Cell A Direct cell to cell contact adhesion proteins Cell B ECM cell to ECM contact
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Specific domain bind to specific cellular receptor
Adhesion proteins Cytoskeletal proteins Integrin Adhesion proteins Specific domain bind to specific cellular receptor spans cell membrane and interact with intracellular protein , Actin filamints
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Collagen Collagen is glycoprotein
28-30 types in human Provides Extracellular framework of animal body The main component of loose connective tissue ,blood vessels ligaments, tendons, bone and skin. The most abundant protein in the body, making 25%-35% of all the whole-body proteins. Collagen is glycoprotein
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Collagen structure Collagen fibers Collagen fibrils
Tropocollagen (triple helix) Single chain of amino acids
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Triple helical collagen supercoils
Collagen structure (Gly –X-Y )n Y proline Glycine X any amino acid Triple helical collagen supercoils (right handed)
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Collagen structure Glycine Proline Lysine ,hydroxylysine
Third amino acid of collagen 33% Proline Y is frequently proline or hydroxyproline 21% of collagen Responsible for left handed alpha helix Lysine ,hydroxylysine Some Y position Form interchain covalent cross link. Form O linked glycosidic bond
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Hydroxyproline and hydroxylysine
Result from hydroxylase enzyme. Hydroxylation need vitamin C TYPE OF POST-TRANSLATIONAL MODIFICATION Hydroxylysine is site for attachment of disaccharide.
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Absent amino acids in collagen
Tryptophan Cysteine
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Biosynthesis 1. Formation of pro-α chains 2. Hydroxylation
3. Glycosylation 4. Assembly and secretion 5. Extracellular cleavage of procollagen molecules 6. Formation of collagen fibrils 7. Cross-link formation Extended Modular Program
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Where is collagen synthesized?
Osteoblast Chondroblast Fibroblast
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1. Formation of pro-α chains
The newly formed polypeptide (prepro-α chains) contain a special signal sequence at their n-terminal ends Directs the passage of the prepro-α chain into the lumen of the RER Then it is cleaved giving a precursor of collagen called a pro-α chain Extended Modular Program
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By prolyl hydroxylase and lysyl hydroxylase enzymes
2. Hydroxylation Proline and lysine residues are hydroxylated to hydroxyproline and hydroxylysine By prolyl hydroxylase and lysyl hydroxylase enzymes Extended Modular Program
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Some hydroxylysine residues are glycosylated with
3. Glycosylation Some hydroxylysine residues are glycosylated with glucose or galactose
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Extended Modular Program
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4. Assembly and secretion
tropocollagen tropocollagen 5. Extracellular cleavage of procollagen molecules Propeptides Extended Modular Program
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6. Formation of collagen fibrils
Extended Modular Program
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Oxidative deamination allysine + hydroxyallysine
7. Cross-link formation Oxidative deamination Cu dependent allysine + hydroxyallysine Covalent crosslink Extended Modular Program
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Extended Modular Program
Summary of biosynthesis Extended Modular Program
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Degradation of collagen
Normal collagen is highly stable Long half life up to several months collagenase
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Covalent crosslink between triple helical units
Lysyl oxidase Cu dependent Oxidatively deaminate some lysyine and hydroxylysine Covalent crosslink Form allysine + hydroxyallysine.
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Difference between collagen helix and alpha helix
Backbone of polypeptide chain twisted about alpha carbon forming a helix Superhelix of 3 chains wrapped around each other in RT haded RT handed twist Each single chain is LT handed Intrachain hydrogen bond interchain hydrogen bond 3.6 aa /turn 3 aa /turn No specific aa sequence. (Glycine X-Y)n
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Collagen structure function relationship
Tight parallel fibers Provide great tensile strength Collagen tendon Arranged at angle to each other. Resist mechanical shear Collagen of bone and teeth Loosely woven ,flexible Collagen of skin Transparent with minimal scattering of light Collagen of cornea of eye Form gel. Viterous humor of eye
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Mention 2 diseases that are related to collage?
1- Scurvey 2- Osteogenesis imperfecta
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Scurvey (Vit. C deficiency)
Defect in hydroxylation of proline and lysine Weak and fragile collagen Collagen become unstable and easily degraded Bleeding per gum, swollen joint, poor wound healing, fragile bone and easily fracture
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Osteogensis imperfecta
Single base mutation Replacement of glycine with bulky amino acid Weak collagen Fragile bone with easily bone fracture from minor trauma
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Elastin Major protein component of elastic tissues such as arteries, lungs, skin Highly cross linked ,insoluble, amorphous Rubber like consistency
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Elastin has no regular 2ry structure ,only random coils
Microfibrils Elastic fibers
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glycine , valine , alanine and proline Little hydroxyproline
Tropoelastin contain glycine , valine , alanine and proline Rich in lysine Little hydroxyproline No hydroxylysine
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Elastic fibers synthesis
Tropoelastin molecules Desmosine crosslink (3 allysyl residues+ unaltered lysine ) lysyl oxidase
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Elastin is highly stable up to 70 years.
Elastin degradation Elastin is highly stable up to 70 years. Elasin is degraded by elastase enzyme releases by neutrophils.
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In lung, elastin is present
Elastin is protected from degradation of elastase by α1 anti-trypsin which inactivate elastase If there is α1 anti-trypsin defficiency Increase elastase activity Increase degradation of elastin Lung emphysema destruction in connective tissue of alveolar wall which cannot be regenerated
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α1- antitrypsin deficiency
Homozygous genetic disease There is deficiency in α1- antitrypsin (α1 antiprotease) Lung emphysema occurs Treated by IV α1- antitrypsin every week.
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Smoking cause oxidation and subsequent inactivation of methionine in α1- antitrypsin.
So, α1- antitrypsin can’t bind to elastase . This will be lead to lung emphysema.
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Differences of elastin from collagen
Many different genetic types Single genetic type Triple helix No (random coils) (Gly-x-y)n No Hydroxylysine is present Contain carbohydrate Intramolecular aldol cross-links Intramolecular desmosine cross-links Widely distributed Large blood vessels,skin ,elastic ligaments High tensile strength + no stretch Stretch+ recoil
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Carbohydrate chain (95%)
Proteoglycans Core protein (5%) Carbohydrate chain (95%) Proteoglycan
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Glycosaminoglycans (GAG)
Core protein Unbranched Long Linear Repeated disaccharide units Amino sugar is sulphated or acetylated Covalent crosslink Disaccharides Amino sugar+ uronic acid
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Proteoglycan monomer is polyanion due to the presence of COO ,SO3
1-The chains of repeating disaccharide units remain separated by repulsion between negative charges- Bottle brush appearance of proteoglycan
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Proteoglycan monomer is polyanion due to the presence of COO ,SO3
2-The chains bind cations as Na and K and attract water by osmotic pressure into ECM- Gel like consistency of ECM
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PROTEOGLYCAN AGGREGATES
Hyalouronic acid PROTEOGLYCAN AGGREGATES Linker protein
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Proteoglycans Proteoglycan monomer Proteoglycan aggregates
Proteoglycan monomer +hyalouronic acid +linker protein(non covalent) Proteoglycan monomer Glycosaminoglycans + core proteins (covalent link)
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Classification of proteoglycan is based on
Disaccharide unit Type of glycosidic bond Degree and location of sulfate group
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Classification of proteoglycan into six groups
Hyaluronic acid (only free GAG, No core protein, non sulfated ) chondroitin sulfate dermatan sulfate heparan sulfate keratan sulfate Heparin (secreted in blood by mast cells,not present in ECM)
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Proteoglycan functions
All the proteoglycan classes determine structural organization of the matrix Each class has also special function
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LAMININ Hetero trimeric
The second most abundant protein in basal laminae after type IV collagen Hetero trimeric Alpha subunit Beta subunit Gamma subunit
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Laminin Functions It can form networks of web like structure to resist tensile force in basal lamina. Bind to type IV collagen ad other components in ECM and integrin ,so provide additional support.
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Fibronectin Glycoprotein of large MW
Formed of 2 identical subunits joined by 2 disulfide bridges.
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Fibronectin Fibronectin has binding sites for : Fibrin Collagen
Heparin DNA Cell surface receptor
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Fibronectin provide a bridge between actin of the cell and ECM
Fibronectin interact with fibronectin receptors (integrin) Integrin interact with actin microfilaments
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Fibronectin Sites ECM Soluble form in plasma
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Fibronectin Functions
Cell migration Communicates exterior of the cell with its interior Bind to the platelets during blood clotting
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How the tumor cells metastasize?
Tumor cells secrete less than normal amounts of adhesion protein Allow more free movements within ECM Increase the potential for the tumor cells to leave their original location
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Medical importance of ECM
Infection spread Metastasis Rheumatoid arthritis Alteration of renal glomeruli Genetic defect Osteogenesis imperfecta Mucopolysaccharidosis
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The link between ECM and disease
1- Infection spread: Infectious agents secrets hyluronidase enzyme which degrade hyalouronic acid. 2- Cancer cell metastasize: Through alternation of integrity of ECM (i.e secret less amount of fibronectin).
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3- Rheumatoid disease and osteoarthitis may occur due to damage in ECM
3- Rheumatoid disease and osteoarthitis may occur due to damage in ECM. 4- Alternation in renal glomeruli will lead to protein excretion in urine. 5- osteogenesis imperfecta 6- Mucopolysaccharidosis: due to defect in lysosomal enzyme which degrade mucopolysaccharides ( old name of GAG)
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Mucopolysaccharidosis
Gradual deterioration of health and death in childhood. Accumulation of large quantities of GAGs in various tissues Defect in normal degradation of molecules of ECM Defeciencies of lysosomal enzymes
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