Why study tissue proteins?
To understand normal body functions .
In inflammatory states
To identify the cause of various genetic and metabolic disorders related
to tissue proteins
In the spread of cancer cells.
Several diseases (eg:Osteogenesis imperfecta and a number of
types of the Ehlers-Danlos syndrome) are due to genetic
disturbances of the synthesis of collagen.
Components of proteoglycans are affected in the group of genetic
disorders known as the mucopolysaccharidoses.
To use and apply them in the medical, industrial, commercial fields.
In food products, cosmetic surgery.
The gelatin used in food and industry is derived from the partial
hydrolysis of collagen.
The Extracellular Matrix
The space outside the cells of a tissue is filled with a composite material
called extracellular matrix(ECM).
This ECM is also known as the connective tissue. It is composed of -
a) Gel with interstitial fluid.
b) 3 major classes of biomolecules:
Structural proteins: collagen, elastin and Keratin(epidermal tissues)
Specialized proteins: e.g. fibrillin, fibronectin, and laminin.
Proteoglycans(Mucoproteins) : Conjugated proteins consisting of
Protein + Carbohydrate(5%-95%)
Carbohydrate part is in the form of Glycosaminoglycans [GAGs].
Thus, the extracellular matrix (ECM) is a complex structural entity
surrounding and supporting cells that are found within mammalian tissues.
Most abundant insoluble fibrous protein in
the connective tissue of mammals.
Makes up about 25% to 35% of the
whole-body protein content.
Scleroprotein secreted from the cells
In greek ‘kolla’ means ‘glue’.Collagen is
also called as glue-producer.
Distribution of collagen varies in different
Also found in mucous membranes,
nerves,Blood vessels, and organs.
Collagen fibers in
Functions Of Collagen
It imparts strength, support, shape
and elasicity to the tissues.
It accounts for 6% of the weight
of strong, tendinous muscles
It provides flexibility, support, and
movement to cartilage.
It encases and protects delicate
organs like kidneys and spleen.
It fills the sclera of the eye in
Teeth(dentin) are made by adding
mineral crystals to collagen.
Collagen contributes to proper
alignment of cells for cell
proliferation and differentiation.
When exposed in damaged blood
vessels, it initiates thrombus
Types Of Collagen
In humans, there are at least 19
distinct types of collagen made up
of 30 distinct polypeptide chains
(each encoded by a separate
They are subdivided into a number
of classes based primarily on the
structures they form
However, 90% of the collagen in
the body are of type I, II, III, and IV.
These types determine the physical
properties of specific tissues and
perform their specialized function.
Structure Of Collagen
The basic structural unit of a
collagen molecule is a triple helix.
Triple helical structure may occur
throughout the molecule or only in a
part of it.
Structure Of type I mature
Triple helical structure occurs
throughout the molecule.
This triple helix is composed
of 3 polypeptide chains twisted
around each other.
Each polypeptide/alpha chain
is in turn a left handed helix with
3 amino acids per turn totally
containing approximately 1000
amino acids per chain.
Alpha chain Triple Helix
Each alpha chain has an unusual
abundance of 3 amino-acids
glycine, proline and hydroxyproline.
Glycine occurs at every third
position in the amino acid sequence
which can be represented as (Gly-X-
X and Y are other amino acids of
which proline and hydroxyproline
occupy 100 positions each.
Glycine occupies the crowded
center of the triple helix as it has a
small side chain[ H atom] where as
Hydroxyproline and proline point
outwards imparting rigidity to the triple
The alpha chains are wound
around each other in a right handed
super helix to form a rod like molecule
1.4nm wide and 300nm long
The triple helices are stabilized by
Hydrogen bonds, covalent cross-
links, electrostatic and hydrophobic
interactions and van der waals forces.
The covalent cross links within and
between the helices are formed by
copper dependent enzyme lysyl
oxidase between the lysine and
These triple helical molecules pack together
side by side to form elongated fibrils.
Fibrils are displaced longitudinally from each
other by 67 nm [one quatter of its length] to form
a quarter staggered arrangement.
Fibrils bundle up to form fibers making up
Cross link formation
Biosynthesis of Collagen
Collagen synthesis occurs in the fibroblasts, osteoblasts in
bone, chondroblasts in cartilage and odontoblasts in teeth.
First synthesized in precursor form of preprocollagen polypeptide chain
in the ribosomes during translation
The leader sequence of amino acids[signal peptide] in the
preprocollagen directs it to enter the lumen of E.R
In the lumen of E.R, the Signal peptide is cleaved to form procollagen.
The proline and lysine amino acids in the procollagen chain undergo
hydroxylation and glycosylation known as post translational
Disulfide bonds are formed between three procollagen chains which
twist around each other to form a triple helix molecule.This step is called
This Procollagen molecule is secreted into the extracellular matrix from
the golgi compartment of the E.R.
Here, the procollagen aminoproteinase and carboxy proteinase
enzymes remove extra terminal amino acids from the procollagen
molecule to form collagen .
The collagen molecules assemble into fibrils and inturn fibers being stabilized
by the covalent cross-links.
Abnormalities associated with collagen
Collagen-related diseases arise from
They affect the biosynthesis, assembly, postranslational modification, secretion, or
other processes involved in normal collagen production.
These include :
Ehler Danlos syndrome
Chondrodysplasias [affects cartilage]
Ehler Danlos Syndrome
Ehlers-Danlos Syndrome is a group of inherited connective tissue disorders.
abnormalities in the synthesis and metabolism of collagen
Mutations in the collagen genes: COL1A1, COL1A2, COL3A1, COL5A1, COL5A2
a deficiency of enzyme lysyl hydroxylase.
A deficiency of procollagenN-proteinase, causing formation of abnormal
thin, irregular collagen fibrils
Mutations alter the structure, production, or processing of collagen or proteins
that interact with collagen
WeakenS connective tissue in the skin, bones, blood vessels, and organs causing-
Poor wound healing.
Alport syndrome is a genetic disorder
glomerulonephritis, endstage kidney
disease, and hearing loss.
It also affects the eyes.
The presence of blood in the
urine[hematuria] is almost always found
in this condition.
Mutations in COL4A3,COL4A4,COL4A5
collagen biosynthesis genes.
These prevent the production or
assembly of the type IV collagen
network in the basement membranes.
kidneys are scarred and unable to filter
waste products resulting in hematuria
and renal disease.
Alport syndrome affecting eyes
• Epidermolysis bullosa refers to a group of
inherited disorders that involve the
formation of blisters following trivial
mutations in COL7A1, affecting the
structure of type VII collagen.
Type VII collagen forms delicate fibrils
that anchor the basal lamina to
collagen fibrils in the dermis.
These anchoring fibrils are reduced in
this form of the disease, causing friction
Blistering and painful sores like third
Osteogenesis imperfecta or Brittle Bone Disease is a
genetic bone disorder due to decrease dcollagen
Mutations in the COL1A1 andCOL1A2 genes
coding for procollagen chains.
Replacement of glycine by another bulkier
amino acid resulting in decreased collagen or
improper procollagen structure forming
Mutations also cause ‘procollagen suicide ‘
All these cause brittleness.
Thin,t ransclucent, blue scleras.
Affected infants may be born with multiple
fractures and not survive.
weak muscles, brittle teeth, a curved spine and
Chondrodysplasias are a mixed
group of hereditary disorders
One example is Stickler
syndrome, manifested by
degeneration of joint cartilage
and of the vitreous body of the
Mutations in the COL2A1
gene, leading to abnormal
forms of type II collagen.
Osteolathyrism is a collagen cross-linking
deficiency caused by dietary over-
reliance on the seeds of Lathyrus sativus
(kesari dal) in some parts of India.
Osteolathyrogenic compounds like Beta-
aminopropionitrile(BAPN) and Beta-
oxalyl aminoalanine [BOAA] found in
Kesari dhal inhibit enzyme lysyl oxidase
required for the formation of cross links
in the triple helices
weakness and fragility of
skin, bones, and blood vessels
Paralysis of the lower extremities
associated with neurolathyrism
Scurvy is a disease due to deficiency of
It is not a genetic disease.
It is related to improper collagen
Vitamin C [ascorbic acid ]is
required as a cofactor for
hydroxylase enzymes during the
hydroxylation of proline and lysine
in the synthesis of collagen.
Deficiency causes impaired
collagen synthesis due to
deficiency of hydroxylases.
Bleeding of gums
Poor wound healing
Uses Of Collagen
Collagen is used as temporary thermoplastic glues in musical instruments like
violin and guitar .
Recently used as a fertilizer
Gelatin derived from the partial hydrolysis of collagen is used in food products like
It is also used in pharmaceutical, cosmetic, and photography industries.
Mild benefit to rheumatoid arthritis patients.
Keeps the valvular leaflets of heart in shape.
Helps in the deposition of calcium during aging.
Used in cosmetic surgery, for burn patients for reconstruction of bone and a wide
variety of dental, orthopedic and surgical purposes.
Main ingredient of cosmetic makeup.
Human collagen is used for immunosuppression during transplantation.