Collagen -Structure and Function

Collagen
The connective tissue protein

Why study tissue proteins?
 To understand normal body functions .
 In development
 In inflammatory states
 Aging process.
 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.

Collagen
 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
called fibroblasts.
 In greek ‘kolla’ means ‘glue’.Collagen is
also called as glue-producer.
 Distribution of collagen varies in different
tissues.
 Also found in mucous membranes,
nerves,Blood vessels, and organs.
90%
85%
70%
4%
bones tendons
skin liver
Collagen fibers in
muscle tendons

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
crystalline form.
 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
formation

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
gene).
 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
Collagen:
 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
Amino-
acids

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-
Y)n.
 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
helix.
 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
[Gly-X-Y]n

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
hydroxylysine residues.
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
tissues.
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
modifications.
 Disulfide bonds are formed between three procollagen chains which
twist around each other to form a triple helix molecule.This step is called
registration.
 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.

Biosynthesis of
collagen from
Preprocollagen

Abnormalities associated with collagen
 Collagen-related diseases arise from
 genetic defects
 nutritional deficiencies
 They affect the biosynthesis, assembly, postranslational modification, secretion, or
other processes involved in normal collagen production.
 These include :
 Ehler Danlos syndrome
 Alport syndrome
 Epidermolysis bullosa
 Osteogenesis Imperfecta
 Chondrodysplasias [affects cartilage]
 Scurvy
 Osteolathyrism

Ehler Danlos Syndrome
 Ehlers-Danlos Syndrome is a group of inherited connective tissue disorders.
 CAUSE
 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
 EFFECT
 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-
 Skin hyperextensibility
 Joint dislocations
 Tissue fragility
 Poor wound healing.

Ehler-Danlos
Syndrome
•Hyperextensibility of
skin
•Hypermobility of
joints

Alport Syndrome
 Alport syndrome is a genetic disorder
characterized by
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.
 CAUSE
 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
• Epidermolysis bullosa refers to a group of
inherited disorders that involve the
formation of blisters following trivial
trauma.
• CAUSE
 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
and blistering.
• EFFECT
 Blistering and painful sores like third
degree burns
Blister
formation

Osteogenesis Imperfecta
 Osteogenesis imperfecta or Brittle Bone Disease is a
genetic bone disorder due to decrease dcollagen
formation.
 CAUSE
 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
abnormal fibers.
 Mutations also cause ‘procollagen suicide ‘
 All these cause brittleness.
 EFFECT
 Thin,t ransclucent, blue scleras.
 Affected infants may be born with multiple
fractures and not survive.
 weak muscles, brittle teeth, a curved spine and
hearing loss.

Chondrodysplasias
 Chondrodysplasias are a mixed
group of hereditary disorders
affecting cartilage.
 One example is Stickler
syndrome, manifested by
degeneration of joint cartilage
and of the vitreous body of the
eye.
 CAUSE
 Mutations in the COL2A1
gene, leading to abnormal
forms of type II collagen.
 EFFECT
 shortlimbed dwarfism
 skeletal deformities.

Osteolathyrism
 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.
 CAUSE
 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
 EFFECT
 weakness and fragility of
skin, bones, and blood vessels
 Paralysis of the lower extremities
associated with neurolathyrism

Scurvy
 Scurvy is a disease due to deficiency of
vitamin C
 It is not a genetic disease.
 It is related to improper collagen
formation
 CAUSE
 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.
 EFFECT
 Bleeding of gums
 Poor wound healing
 Subcutaneous hemorrhages

Uses Of Collagen
 Industrial Uses
 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
desserts, jellies.
 It is also used in pharmaceutical, cosmetic, and photography industries.
 Medical uses
 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.

Collagen -Structure and Function

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