Dr.S.Chakravarty MBBS, MD

Describe the structure and formation of collagen and elastin

List the various steps in Post translational modification of collagen

Mention the role of Vitamin C and copper in stabilizing the collagen
structure

List the types of collagen and its distribution in the body

Describe the defects of collagen and elastin and its associated clinical
conditions
2

Fibrous proteins – collagen, elastin

Specialised proteins – Laminin, Fibronectin

Gel forming – Proteoglycans
3

Regulation of proliferation, differentiation,
migration and cell-cell recognition

Prevents or limits the movement of bacteria and
cancer cells

Damage leads to various diseases like
osteoarthritis, Glomerulonephritis etc.
4

Alpha helical secondary structure.

Low water solubility

A long narrow rod like structure.

Role in determining cellular structure and function.
5
- most abundant protein in body; rigid,
insoluble.
stretchy, rubber-like, lungs, walls of large
blood vessels, ligaments
- tough fibers (hair, nails, outer epidermis)
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
Dispersed as a gel – Vitreous humor

Tight parallel fibres – Tendons

Stacked for minimal scattering – Cornea

Mechanical shearing – Bone.
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Fibril forming
Tissue
Function
Type 1 (90%)
Tendon, bone, ligaments and skin
Resistance to tension
Type 2
Hyaline and elastic cartilage
Resistance to pressure
Type 3
Skin, muscle, blood vessels
Structural framework for
expanding tissues
Network
forming
Tissue
Function
Type 4
Basement membrane
Filtration and support
Anchoring fibrils Tissue
Function
Type 7
Anchors basal cells to underlying
stroma
Epithelium
Type I collagen is stronger than steel !!
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9
1.
Molecular collagen (pre pro collagen and pro
collagen) – soluble
2.
Microfibrils – tropocollagen ( insoluble)
3.
Fibrils
4.
Fibres
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Usmle!
Left handed
helix
3 such strands
wound together

About 25-30% of the total weight of body is collagen.

Major fibrous element of tissues like bone , teeth ,
tendons , cartilage and blood vessels.

Each polypeptide has about 1000 amino acid residues.

1/3 of the a.a are Gly residues i.e every 3rd residue is
glycine.

The repetitive a.a sequences can be denoted by Gly-X-Y
, where X and Y are commonly Proline and
Hydroxyproline .

The collagen is a rod like structure .

The three polypeptide chains are held in a helical
conformation by winding around each other.This
results in formation of a superhelical cable with 3.3
amino acids per turn and each turn separated by
2.9 A.

The strands are H-bonded to each other ( Hdonated by NH grp and H-accepted by C=O )

Further stabilization by H –bonds between OHgroups and the bridging water molecules.
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
Quarter staggered Arrangement



The trophocollagen molecules are arranged in in such a
way that each row moves ¼ length over last row and the
5th row repeats the same position of the first row.
Molecules in each row separated by 400 A and adjacent
and adjacent rows by 680 A.
The collagen fibres are further strengthened by
covalent cross links b/w lysine and hydroxy-lysine
Formation of pro alpha chains: with signal sequence at N-terminal ends.
Removal of signal sequence
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
Hydroxylation of proline and lysine

Requires a dioxygenase with Fe .
USMLE concept!
 (Vit C keeps the iron reduced )


Glycosylation – hydroxylysine with glucose.
Spontaneous disulfide bond formation at C terminal
peptides
formation of triple helix.
3.
cellular matrix.
and release of pro-collagen to extra
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
Stabilizing force
 H-bonding between Gly of one chain and Pro of another
 ~1 H-bond per triplet

Extra cellular cleavage of N and C-terminal propeptides
– pro collagen peptidases.
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
Terminals (ends) of the triplehelix are different
 C-telopeptides
 N-telopeptides
(from Kadler, 1996)

Terminals are non-helical

Helps in triple helix
formation
N-TERMINAL INTRACHAIN
DISULPHIDE BONDS
 C-TERMINAL- INTERCHAIN +
INTRACHAIN DISULPHIDE
BONDS

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Elevated levels can be used in the confirmation of increased bone
turnover.
Elevated levels can identify persons with osteoporosis who have
elevated bone turnover and who, as a result, are at increased risk for
rapid disease progression.
The patient's response to antiresorptive osteoporosis treatment can be
monitored through this test.
This test can be used to monitor and assess how effective
antiresorptive therapy has been in patients treated for disorders such
as osteopenia, osteoporosis, and Paget disease.
This test can also serve as an adjunct means of monitoring
patient response to other treatments for diseases with increased bone
turnover, such as rickets & osteomalacia.
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Cross links formed by
lysyl/prolyl oxidase
Oxidative deamination of lysines
and hydroxylysines forms
Allysine (aldehyde)
This reacts with amino group of
nearby lysine or hydroxylysine to
form interchain cross-link.
Very important for tensile
strength of collagen.
USMLE
concept !
Cu2+/
vitamin B6

Excessive cross links
problem in OLD AGE
Hardening of
ligaments
(STIFF)Prone to tear

Less cross links 
Weak collagen

Menke’s disease
due to decreased
Cu (discussed later)
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Covalent X-links
between Allysine
and
hydroxylysine
Tropocollagen
molecule
triple helix of
a-chains.
Kaplan USMLE step 1
lecture notes
28



Helps in retaining the
shape after stretching.
Connective tissue
protein.
lungs, large blood
vessels, elastic
ligaments
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
Outer cover - Microfibrils containing fibrillin and
microfibril associated glycoproteins (15%)

Core of amorphous elastin –single polypeptide
chain of 800 amino acids-85%

Non-polar amino acids – gly, ala, val. Also rich in
pro, lysine. ( no OH-proline or OH-lysine)
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Elastin
• 3D network of cross-linked
polypeptides – (tropo elastin)
• cross links involve Lys and alLys –lysyl
oxidase
• 4 Lys can be cross-linked into
desmosine
• Desmosines account for elastic
properties
Desmosine


6
Elastin interconverts between a number of conformations, both
disordered (upper two on left) and b-spiral (bottom left).
After cross-linking, when elastin is stretched (or compressed) it is
less stable and it returns to the disordered conformations.
NH
HN
HC CH2 CH2 CH2 CH2 HN
O
CH2 CH2 CH2 CH2 CH
O
lysinonorleucine
O
NH
CH
CH 2
CH 2


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Some lysine residues in elastin
are deaminated and oxidized
to the aldehyde level.
They combine with each other
and with other lysines to form
lysinonorleucine and
desmosine cross-links
O
CH 2
O
CH
CH2
CH2 CH2 CH
CH2
HN
HC
+
CH
NH
CH2
desmosine
USMLE
concept !
CH2
CH2
CH2
HC HN
O
NH
Major Differences Between Collagen and Elastin
Collagen
1. Many different genetic types
Elastin
One genetic type
2. Triple helix
No triple helix; random coil
conformations permitting stretching
3. (Gly-X-Y)n repeating structure
No (Gly-X-Y)n repeating structure
4. Presence of hydroxylysine
No hydroxylysine
5. Carbohydrate-containing
No carbohydrate
6. Intramolecular aldol cross-links
Intramolecular desmosine cross-links
7. Presence of extension peptides
biosynthesis
No extension peptides present during
during biosynthesis

Serine type elastase: neutrophils, macrophages,
fibrblasts.

Matrix metalloproteinases – mmp-12 and 7,
gelatinases.
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
Keratin is rich in cysteines.

Its secondary structure is mostly a-helical.

The helices form coiled coils (on right).

The coiled coils pack into higher order elongated2 nm
structures.

Keratin properties depend strongly on the degree
of disulfide cross-linking.


8
With low levels of cross-linking, it is flexible (hair, skin).
It can be made very hard with additional cross-linking
(claws, horns).

The structure of
keratin is
strengthened by
disulfide crosslinks from one
helix to another.
O
O
HS CH2 CH
CH CH2
SH
NH
two
cysteines
NH
O
O
CH CH2
NH
10
S
S CH2 CH
disulfide
cross-link
NH






Malaise , Lethargy
Poor wound healing
Bleeding gums
Weak bones
Petechiae over skin
Anaemia
39
1498
40
41

A culture of fibroblast cells is provided with equal
all the 20 amino acids. After 10 days , the
concentration of the amino acids is assessed .Which
amino acid will have the lowest concentration?

A. Lysine
B.methionine
C.Glycine
D.proline
E.Cysteine




42
1.
Elastin fibres in the alveolar walls of the lungs can be stretched easily
during inspiration and recoil to their original shape once the force is
released. This process facilitates expiration. The property described can
be best explained by:
a)
Heavy posttranslational hydroxylation
High content of polar amino acids
Chain assembly to form a triple helix
Interchain crosslinks involving lysine
Abundant interchain disulfide bridges
b)
c)
d)
e)
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3. A 14-year old male presents to your office complaining of easy
bruising. Physical examination reveals soft and loose skin as
well as multiple ecchymoses in the forearm and pretibial
regions. Histologic evaluation with electron microscopy shows
collagen fibrils that are abnormally thin and irregular. Which of
the following stages of collagen synthesis is most likely
impaired in this patient?
a)
b)
c)
d)
e)
RNA signal sequence recognition
Amino acid incorporation into polypeptide chain
Triple helix formation
Lysine residue hydroxylation
cleavage of propeptides
44