Collagen is the most abundant protein in the human body and provides structure and strength. It has a unique triple helix structure that gives tissues their tensile strength. There are over 20 types of collagen that are classified based on structure and function. Collagen synthesis involves transcription of genes, modification and assembly of procollagen monomers in the ER and Golgi, and extracellular processing and crosslinking to form mature collagen fibrils. Mutations in collagen genes or defects in processing can lead to heritable disorders like osteogenesis imperfecta or Ehlers-Danlos syndrome. Collagen supplements are used cosmetically to improve skin properties.
3. Evidence of regular structure was presented in 1930’s.
Ramachandrn, concentrated on the conformation of the
collagen monomer .
Dealing with the confirmation of each polypeptide chain gave the
triple helix “Madras” model.
Madras model is the most widely accepted model which gave the
quaternary structure of collagen
History:
4. INTRODUCTION
Collagen is a type of fibrous protein
Shares the common features of fibrous proteins like :
- Polypeptide chains organized approximately parallel along a
single axis
- Insoluble in water and dilute salt solution.
- Gives strength and flexibility to the structure.
Other examples
Elastin
Keratin.
5. Most abundant protein in human body
Makes 25% to 35% of whole body protein content.
Comes from Greek word “kolla” meaning “Glue producer”
Long rigid structure with three polypeptide chains
Forms rope like triple structure.
Present in tendons, ligaments, skin, cornea, cartilage, bone,
blood vessels, gut, intervertebral disc.
Variation in amino acid sequence defines properties
6. STRUCTURE
Tropocollagen is a basic structural unit
Consist of 3 polypeptide chains (α- chains) having about 1000
residues in each chain.
Each α- chain is left handed
Approximately 3 amino acid residue per turn.
300 nm long; 1.5 nm diameter.
Each of the 3 polypeptide chains are held in a helical
conformation by winding around each other.
7. 3 left-handed chains are super twisted about each other to
form a right-handed triple helix.
Opposite direction of coiling resists unwinding.
Super coils are stabilized by H- bonding between
individual polypeptide chain.
9. Amino acid sequence:
Amino acid sequence in collagen is unique.
Glycine occupies every third position.
Repetitive amino acid sequence may be represented
as Gly–X–Y, where X is frequently Proline and Y is
hydroxyproline or hydroxylysine.
10. • Proline facilitates the formation of the helical
conformation of each α-chain because its ring structure
causes "kinks“ in the peptide chain .
• Glysine fits into the restricted spaces where the three
chains of the helix come together.• Hydroxyproline occurs once in
about 10 amino acid residue.
• Hydroxylysine occurs once in
200 amino acid residue.
11. Hydoxyproline and
Hydroxylysine:
Residues result from hydroxylation of some of proline and
lysine residues.
Hydroxylation of proline gives hydroxyproline
Hydroxylation of lysine gives hydroxylysine.
These residues are rarely present in other proteins.
These are Post -translational modification
Hydroxyproline maximize H bond formation so increase
stabilization of triple helix.
12. Triple helix structure:
Tertiary structure of collagen.
Three helical polypeptide chains linked with each other by
H- bond to form triple helix.
Might be homotrimer or heterotrimer
Amino acid present on surface of the helical molecules
13.
14. Types of collagen:
More than 20 collagen types
Variations in the amino acid sequence of the α-
chains creates the differences
These α-chains are combined to form the various
types of collagen found in the tissues
For example:
The most common collagen , type I contains two
chains called alpha 1 and one chain called alpha 2
Whereas type II collagen contains three alpha 1
chains
15. The collagens can be organized into two groups
1. Fibrilar:
Type I, II, III , V ,VI
Rope like structure
Banding pattern in EM
It reflects the regular staggered packing of the
individual collagen molecules.
Type I: Tendon, Cornea
Type II: Cartilage
Type III: Blood vessels
19. Biosynthesis:
Polypeptide precursors of the collagen molecule are
formed in fibroblasts, osteoblasts, chondroblast
Secreted into the extracellular matrix
Enzymatic modification takes place forming the
mature collagen monomers
Aggregate and cross-linked to form collagen fibrils
20. Steps in biosynthesis:
Transcription of mRNA
Pre- Pro peptide Formation
Pre –Pro peptide to procollagen
Golgi Apparatus modification
Formation of tropocollagen
Formation of collagen fibril
21. Pre–Pro Peptide Formation
• About 34 genes are associated for coding specific mRNA
sequence.
• mRNA then exits from nucleus, enters cytoplasm.
• Then it links with ribosomal subunit for translation.
• Translation produce Pre pro peptide or pre pro alpha chain.
• N terminal of this peptide has special amino acid sequence
called signal sequence
• This is recognized by the a signal recognition particle in
endoplasmic reticulum.
• Directs the peptide to ER.
22. Formation Of Procollagen
Three modifications of the pre-pro-peptide occur leading to the
formation of the alpha peptide:
The signal peptide on the N-terminal is dissolved, and the molecule
is now known as propeptide (not procollagen).
Hydroxylation of lysines and by the enzymes 'prolyl hydroxylase'
and 'lysyl hydroxylase'
Glycosylation occurs by adding either glucose or galactose
monomers onto the hydroxyl groups that were placed onto lysines,
but not on prolines.
Three of the hydroxylated and glycosylated propeptides twist into a
triple helix forming procollagen. Procollagen still has unwound
ends, which will be later trimmed.
23. Hydroxylation:
Proline and lysine residues found in the Y-position of the Gly-
X-Y- sequence can be hydroxylated to form hydroxyproline
and hydroxylysine residues.
Hydroxyproline stabilize the triple helix.
Hydroxylysine permits cross linking of helices to form fibres.
Hydroxylation is enzymatic reaction with ascorbic acid as co-
factor.
Ascorbate or ascorbic acid increase synthesis of collagen by
8 folds. (Murad et.al).
24. Glycosylation:
The hydroxyl group of the hydroxylysine residues of
collagen may be enzymatically glycosylated.
Glucose and Galactose are attached to polypeptide
chains
This addition results in twisting of the chain.
25. Golgi Apparatus Modification :
Three helical pro-α-chains assemble.
Forms Pro–collagen with twisted portion at center and loose
ends on either sides.
The Pro-collagen molecules are then translocated to the Golgi
apparatus, where they are attached to oligosaccharides and
packaged in secretory vesicles.
The vesicles fuse with the cell membrane, causing the release
of Pro-collagen molecules into the extracellular space.
26. Formation of Tropocollagen
• The procollagen molecules then are cleaved by N- and C-
pro-collagen peptidases, which remove the terminal
propeptides, releasing triple-helical molecules.
• This molecule is termed as tropocollagen.
• Absent when synthesizing the type III (Fibrillar collagen )
27.
28. Formation of collagen fibrils:
Individual collagen molecules spontaneously associate to form
fibrils.
They form an ordered, overlapping, parallel array, with
adjacent collagen molecules arranged in a staggered pattern,
each overlapping its neighbour by a length approximately
three-quarters of a molecule.
Called “ Quarter staggered arrangement’’
29. Cross-link formation:
• The fibrillar array of collagen molecules serves as a substrate
for lysyl oxidase.
• This extracellular enzyme oxidatively deaminates some of the
lysyl and hydroxylysyl residues in collagen.
• The reactive aldehydes that result (allysine and
hydroxyallysine) can condense with lysyl or hydroxylysyl
residues in neighboring collagen molecules to form covalent
cross-links .
The cross-linking is essential for achieving the tensile strength
necessary for proper functioning of the connective tissue.
30.
31.
32. Degradation of collagen
Highly stable; t1/2 several months
Remodeled in response to growth or tissue injury
Breakdown depends on proteolytic action of collagenase
The organism Clostridium histolyticum conatins the
enzyme collagenase
Cleave collagen fibres into smaller fragments that can be
phagocytosed and further degraded by lysosomal
enzymes to their constituent amino acids.
34. Medical importance:
Cosmetic surgery.
Bone grafting
Construction of artificial skin substitutes
Hemostatic properties
35. Collagen Abnormalities:
Can be due to:
Defect in expression of collagen gene.
Molecular defect in processing/synthesis
Defect in structure of collagen
36. Scurvy
Resulting from Vitmin C deficiency
Presented as malaise , lethargy , spongy gums ,
bleeding from the mucous membranes
The reaction affected is the hydrxylation of proline
and lysine
InterchaingH bond formation impaired
Capillary fragility leads to sub cutaneous
extravasations of blood
37. Osteogenesis imperfecta:
• Also known as brittle bone syndrome
• Heterogenous group of inherited disorders.
• Mutation in COL1A1 and COL1A2
• Replacement of single Glycine residue by
bulkier amino acid in Type I collagen.
• Symptoms depends on types
• Blue sclera, loss of hearing, retarded wound
healing and a rotated and twisted spine leading
to "humped-back" appearance are common
features
38. Pathophysiology based on the steric hindrance created
by the bulge produced due to bulkier amino acids
There are around 8 types of OI but type 1 is more
common
Type I- Present in early infancy with features
secondary to trauma
Type II-More severe , pulmonary hypoplasia in utero
or during the neonate
39. Ehlers-Danlos Syndrome (EDS):
Inherited connective tissue disorder.
Result from a deficiency of collagen-processing enzymes
(e.g, lysyl oxidase or pro-collagen peptidase), or from
mutations in the amino acid sequences of collagen.
Mutation in genes COL1A1, COL1A2, COL3A1,
COL5A1, COL5A2
Alters the structure, production or processing of
collagen.
40. Signs and symptoms:
Hyper flexibility of joints
Unstable joints
Osteopenia
Stretching and fragile skin
Easy bruising and poor wound healing
Cardiovascular disorders
Valvular disease
Aneurysm
41. Some of the lysyl side chains of the tropoelastin
polypeptides are oxidatively deaminated by lysyl
oxidase, forming allysine residues.
Three of the allysyl side chains plus one unaltered lysyl
side chain from the same or neighboring polypeptides
form a desmosine cross-link .
This produces elastin- an extensively interconnected,
rubbery network that can stretch and bend in any direction
when stressed, giving connective tissue elasticity.
42. Nicolos Paganini Italian violinist had EDS
This rare syndrome helped him play the violin
extraordinarily
The India rubber man , elastic lady are
other personalities described in history having
EDS
43. Alport Syndrome
Is the designation applied to a number of genetic
disorders (both X-linked and autosomal) affecting the
structure of type IV collagen fibers
The presenting sign is hematuria, and patients may
eventually develop end-stage renal disease
Characteristic abnormalities of the structure of the
basement membrane and lamina
44. Epidermolysis Bullosa
Mutations in COL7A1
Presented as skin breaks and blisters as a result
of minor trauma
VII collagen is responsible for anchoring the basal
lamina to collagen fibril in dermis
Anchoring fibrils are reduced
48. Cosmetics and Collagen
Fish collagen peptides are used extensively
The products claims to increase in the total collagen in
body
To improve skin elasticity , smoothness and moisture
Some articles have proved to reduce the wrinkles by
wrinkle replica analysis ( Bourmand et al )
49. References:
Lehninger-Principles of Biochemistry 5th edition.
Lippincott’s Biochemistry 4th edition.
Harper’s Illustrated Biochemistry 26th edition.
Harrison’s Principle of Internal Medicine 17th edition.
www.authorstream.com
Balasubramanian, D . (October 2001). "GNR — A Tribute". Resonance.
Indian Academy of Sciences. 6 (10). Archived from the original on 2014-
01-10.
Beighton, P. (1970) The Ehlers-Danlos Syndrome. William Heinemann
Medical Books Ltd, pp. 1–194. Beighton, P. (1993) The Ehlers-Danlos
syndrome. In: Mckusi
Borumand M, Sibilla S. Effects of a nutritional
supplement containing collagen peptides on skin
elasticity, hydration and wrinkles. J Med Nutr Nutraceut
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