Download - Fibrous protein
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Khuram Aziz
M Phil BIOCHEMISTRY
Junior Scientist by IBC
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Fibrous Proteins
Overview Collagen and Elastin Existance
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OVER VIEW
Collagen and Elastin are the examples of fibrous proteins.
These are basic structural elements. These proteins have special mechanical
properties. They are found as components of skin,
connective tissue, blood vessels, sclera and cornea of eye.
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Collagen
Introduction Types
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Collagen
Structure
1. Amino acid sequence
2. Triple-helical structure
3. Hydroxyproline and Hydroxylysine
4. Glycosylation
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Amino Acid Sequence: Collagen is a glycoprotein
containing galactose and glucose as the carbohydrate content.
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Glycine is one - third of total amino acid content of collagen followed by hydroxyproline and proline account for another one-third of amino acid content of collagen.
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Proline - facilitate the formation of helical conformation of α- chain, because its ring structure causes kink in the peptide chain.
Glycine- found in every third position of the polypeptide chain. It fits into the restricted spaces where the three chains of the helix come together.
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Glycine is the part of the repeating sequence.
Gly- X-Y X- is frequently proline Y- hydroxy proline or hydroxylysine.
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Triple- helical structure: Amino acids side chains are on the
surface of the triple helical molecule.
This allows bond formation between the exposed R- groups of neighboring collagen monomers- This leads to aggregation into fibrils.
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Collagen Triple Helix Prolines, especially hydroxylated
prolines, keep the individual chains extended, and increase Tm (keep it above body temperature).
The small size of the glycine sidechain in every third position allows the three strands to come close together.
There are interstrand hydrogen bonds. It is not very extensible because it is
already extended (3.1 D per residue vs 1.5 D for -helix).
Glycosylation of hydroxylysines appear to modulate fibril or sheet formation by the triple helices.
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Hydroxyproline & Hydroxylysine: Hydroxylation of Proline & lysine residues
after their incorporation into the polypeptide chains.
Thus called post translational modification.
Causes stabilization of triple helical structure.
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Glycosylation: Hydroxyl group of hydroxylysine
residues of collagen are enzymatically glycosylated.
Most commonly glucose and galactose are attached.
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BIOSYNTHESIS OF COLLAGENPrecursors: Collagen is one of the proteins that
functions outside the cell.
Polypeptide Precursors of the collagen molecule are formed in Fibroblast, osteoblasts and chondroblasts.
These are secreted into the extracellular matrix.
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Formation of Pro- α-chains Hydroxylation: Glycosylation Assembly and Secretion Extracellular cleavage of Procollagen
molecules Formation of collagen fibrils Cross-link formation
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1. Formation of Pro- α-chains: Pre-pro α-chains- contain a special amino
acid sequence at their N-terminal. This sequence acts as a signal that the
newly synthesized polypepetide is destined for function out side the cell.
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This sequence facilitate the binding of ribosomes to the rough endoplasmic reticulum (RER), and direct the Pre-pro α-chain into the lumen of the RER.
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This sequence is cleaved in the lumen of RER and after its cleavage Precursor of collagen is formed.
This precursor is called Pro α-chain.
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2. Hydroxylation: Processing of Pro α-chains occur by a
number of enzymic steps in the lumen of RER, while the polypeptides are still being synthesized.
Proline and lysine residues are hydroxylated.
This reaction requires O2 and vitamin C.
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Enzymes are prolyl hydroxylase and lysyl hydroxylase.
In Vit C deficiency, collagen fibers cannot cross link- and tensile strength is decreased (scurvy).
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3. Glycosylation: Modified by glycosylation with glucose
or galactose residues.
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4. Assembly and Secretion: After hydroxylation and glycosylation-
Pro α-chains are converted to Pro-collagen. Pro-collagen has a central region of triple
helix and its ends have non-helical regions of amino and carboxyl terminal extensions .
These extensions are called Propeptides.
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In the formation of procollagen interchain disulfide bonds are formed between the C- terminal extensions of the pro α-chains.
This alignment of pro α-chains is favorable for helix formation.
Then pro-collagen chains are translocated to Golgi- apparatus.
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In the golgi they are packaged in secretory vesicles.
These vesicles fuse with the membrane and release the pro-collagen molecule into the extracellular space.
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5. Extracellular cleavage of Procollagen molecules:
After their release the Procollagen molecules are cleaved by N- and C Procollagen peptidases.
These remove the terminal Propeptides.
Triple helical structure is released as Tropocollagen.
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6. Formation of collagen fibrils: Tropocollagen spontaneously associate
with each other and form collagen fibrils.
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7. Cross-link formation: The fibrils that are formed become a
substrate for lysyl oxidase. It contains copper. It oxidatively deaminates lysyl and
hydroxlysyl residues in collagen. Reactive aldehydes- Allysine and
hydroxylysine are formed.
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These aldehydes the react with the neighboring lysyl and hydroxlysyl and covalent cross links are formed.
This cross-linking leads to the formation of mature collagen.
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Biosynthesis of Collagen
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Procollagen and Tropocollagen Formation
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Aggregation and Cross-linking
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Formation of Cross-linkages
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Lect. 6-35
Electron micrographs of colagen fibers showing band pattern
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Locations and events involved in collagen biosynthesis Rough Endoplasmic Reticulum Synthesis of preprocollagen Insertion of procollagen molecule into
the lumen of ER.
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Lumen of ER: Hydroxylation of proline and lysine
residues. Glycosylation of selected hydroxylysine
residues.
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Lumen of ER and Golgi apparatus: Self assembly of tropocollagen molecule
(disulfide bond formation).
Secretory vesicles:
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Degradation of collagen: Collagen highly stable molecule. Half life is several years. Breakdown- collagenases
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Collagen diseases
Ehlers- Danlos Syndrome
Osteogenesis Imperfecta syndrome.
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Ehlers-Danlos syndrom (EDS)
Heterogeneous group of generalized connective tissue disorder
Inheritable defect in metabolism of fibrillar collagen
Deficiency of lysyl hydroxylase or procollagen peptidase enzyme
Or mutation in the amino acid sequence of type I, III, or IV collegen
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Ehlers-Danlos syndrom (EDS)
Fragile, stretchy skin Loose joints Potentially lethal vascular problems
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Osteogenesis Imperfecta (OI)
Also known as brittle bone disease Heterogeneous group of inherited
disorder distinguished by bones which can easily bend and fracture
Defect Presentation Sign and Symptoms Types
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Elastin
Introduction Occurrence Structure--- insoluble protein polymer
synthesized from a precursor tropoelastin (700 A.A) primarily small and non-polar
Tropoelastin deposits on glycoprotein (fibrillin)
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Elastin
Role of lysyloxidase
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Lect. 6-47
Desmosine is formed from 4 lysines, 3 of which are oxidised.
Desmosine
CH
NH
CO
CH2 CH2 CHOCH2 CH
NH
CO
CH2CH2CHO CH2
Lysine
Allysine
CH
NH CO
CH2
CH2
CH2
CH2
NH3+
CH
NHCO
CH2
CH2
CH2
CHOAllysine
Allysine
CH
NH
CO
CH2 CH2 CH
NH
CO
CH2CH2
CH
NH CO
CH2
CH2
CH2
CH2
N+
CH
NHCO
CH2
CH2
CH2
CC
C
C
C
Desmosine
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Elastin Marfan syndrome--- a connective
tissue disorder characterized by 1. Impaired structural integrity in the
skeleton2. The eye3. And the cardiovascular system The defect is abnormal fibrillin protein
(functional microfibrils are not formed)
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Elastin Degradation
Alpha 1-Antitrypsin Role in the lungs Deficiency
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Learning Resources
Lippincott’s Biochemistry Harpers Biochemistry Teacher Notes