Collagen and elastin are fibrous proteins found in the extracellular matrix that provide structure. Collagen is the most abundant protein in the body and forms rope-like triple helices from three polypeptide chains. There are over 25 types of collagen that form fibrils, networks, or are associated with fibrils. Collagen synthesis involves post-translational modifications before assembly into fibers and crosslinking outside cells. Abnormalities in collagen synthesis and structure can cause disorders like Ehlers-Danlos syndrome and osteogenesis imperfecta.

1. EXTRACELLULAR
MATRIX
Muti ullah

2. EXTRACELLULAR MATRIX
• Collagen and elastin are examples of common
fibrous proteins of the extracellular matrix that
serve structural functions in the body.
• Collagen and elastin are found as components of
skin, connective tissue, blood vessel walls, sclera
and cornea of the eye.

3. COLLAGEN:
• Collagen is the most abundant protein in the
human body.
• A collagen molecule is a long structure in which
three polypeptides (referred to as “α chains”) are
wound around one another in a rope-like triple
helix.

4. • In some tissues, collagen may be dispersed as a gel
that gives support to the structure, as in the
extracellular matrix or the vitreous humor of the
eye.
• In other tissues, collagen may be bundled in tight,
parallel fibers that provide great strength, as in
tendons.

5. TYPES OF COLLAGEN:
• The collagen superfamily of proteins has more than
25 types.
• The three polypeptide α chains are held together
by hydrogen bonds between the chains.
• These α chains are combined to form the various
types of collagen found in the tissues.

6. CLASSIFICATION OF COLLAGEN:
FACITs = fibril-associated collagens with interrupted triple
helices.

7. 1. Fibril Forming Collagens:
• Types I, II, and III are the fibrillar collagens.
• They have the rope-like structure.
• Type I collagen fibers have supporting property of
high tensile strength (for example, tendon and
cornea).
• Type II collagen molecules are restricted to
cartilaginous structures.
• Type III collagen are prevalent in more distensible
tissues, such as blood vessels.

8. 2. Network Forming Collagens :
• Types IV and VIII form a three dimensional mesh,
rather than distinct fibrils.
• For example, type IV molecules assemble into a
sheet or meshwork that constitutes a major part of
basement membranes .

9. 3. Fibril Associated Collagens :
• Types IX and XII bind to the surface of collagen
fibrils, linking these fibrils to one another and to
other components in the extracellular matrix.

10. Triple Helical Structure:
• Collagen although is a fibrous protein but it has an
elongated, triple-helical structure that is stabilized
by inter-chain hydrogen bonding.

11. STRUCTURE:
•Amino acid sequence :
• Collagen is rich in proline and glycine, both of which are
important in the formation of the triple-stranded helix.
• Proline facilitates the formation of the helical
conformation of each α chain because its ring structure
causes “kinks” in the peptide chain.
• Glycine is found in every third position of the
polypeptide chain.

12. • The glycine residues are part of a repeating sequence
–Gly–X–Y–
where
• X is frequently proline.
• Y is often hydroxyproline.
• Thus , most of the α chain can be regarded as a poly-
tripeptide whose sequence can be represented as (–
Gly–Pro–Hyp–).
• While X and Y can be any other amino acids, about 100
of the X positions are proline and about 100 of the Y
positions are hydroxyproline.

13. Hydroxyproline and Hydroxylysine:
• Collagen contains hydroxy-proline and hydroxy-lysine,
which are not present in most other proteins.
• These residues result from the hydroxylation of some
of the proline and lysine residues after their
incorporation into polypeptide chains. The
hydroxylation is, thus, an example of post- translational
modification.
• Generation of hydroxy-proline maximizes formation of
inter-chain hydrogen bonds that stabilize the triple
helical structure.

14. Glycosylation:
• The hydroxyl group of the hydroxy-lysine residues
of collagen may be enzymatically glycosylated.
Most commonly, glucose and galactose are
sequentially attached to the polypeptide chain
prior to triple helix formation.

15. BIOSYNTHESIS:
• The polypeptide precursors of the collagen
molecule are synthesized in fibroblasts.
• They are enzymatically modified and form the
triple helix, which gets secreted into the
extracellular matrix.
• After additional enzymatic modification, the
mature extracellular collagen monomers aggregate
and become cross-linked to form collagen fibers .

17. 1. Formation of pro-α chains :
• The newly synthesized polypeptide precursors of α-chains
(pre-pro-α chains) contain a special amino acid sequence at
their N-terminal ends.
• This sequence acts as a signal that forces this polypeptide
(being synthesized) to be secreted from the cell.
• The signal sequence helps in the binding of ribosomes to
the rough endoplasmic reticulum (RER)
AND
• Directs the passage of the pre pro-α chain into the lumen of
the RER. The signal sequence is rapidly cleaved in the RER to
yield a precursor of collagen called a pro-α chain.

18. 2. Hydroxylation:
• The pro-α chains are processed by a number of enzymatic steps within the lumen of the
RER.
• Proline and lysine residues found in the Y-position of the –Gly–X–Y– sequence can be
hydroxylated to form hydroxy-proline and hydroxy-lysine residues.
• These hydroxylation reactions require certain co-factors.
• molecular oxygen.
• Ferrous ions.
• vitamin C.
• In case of vitamin C deficiency, absence of hydroxylation reactions occur, due to which
interchain H-bonding is impaired.
• Collagen fibers are also not cross-linked, greatly decreasing the tensile strength of the
assembled fiber. The resulting disease is known as scurvy.

19. 3. Glycosylation:
• Some hydroxy-lysine residues are modified by
glycosylation with glucose or galactose.

20. 4. Assembly and secretion:
• After hydroxylation and glycosylation, three pro-α
chains form pro-collagen.
• The formation of pro-collagen begins with formation of
interchain disulfide bonds between the C-terminal
extensions of the pro-α chains.
• The pro-collagen molecules move through the Golgi
apparatus, where they are packaged in secretory
vesicles.
• The vesicles fuse with the cell membrane, causing the
release of pro-collagen molecules into the extracellular
space.

21. 5. Extracellular cleavage of
procollagen molecules :
• After their release, the pro-collagen molecules are
cleaved by pro-collagen peptidases ,which remove
the terminal propeptides releasing triple-helical
tropo-collagen molecules .

22. 6. Formation of collagen fibrils :
• Tropo-collagen molecules spontaneously associate
to form collagen fibers.
• They form an ordered, overlapping, parallel array,
with adjacent collagen molecules arranged in a
staggered pattern.

23. 7. Cross link formation:
• The fibers of collagen molecules serves as a substrate for lysyl oxidase.
• This copper containing extracellular enzyme deaminates some of the
lysine and hydroxy-lysine residues in collagen.
• The reactive aldehydes that result (allysine and hydroxyallysine) can
condense with lysine or hydroxy-lysine residues in neighboring collagen
molecules to form covalent cross-links and mature collagen fibers.

24. DEGRADATION:
• Normal collagen molecules are highly stable having half lives as long as several
years.
• Breakdown of collagen fibers is dependent on the proteolytic action of enzyme
collagenases.
• For type I collagen, the cleavage site is specific, generating three-quarter and
one-quarter length fragments .
• These fragments are further degraded by other matrix proteinases .

25. Abnormalities in Collagen:
Ehlers Danlos syndrome :
• It is a heterogeneous group of connective tissue disorder.
• It is an inheritable defect.
• 10 different types are found till now.
• It can be caused by:
1.Deficiency of collagen-processing enzymes
a. lysyl hydroxylase
b. N-procollagen peptidase
2. Mutations in the amino acid sequences of collagen types
I, III, or V.

26. CLASSIC TYPE:
• It is due to defect in collagen type V.
• It is characterized by skin extensibility, skin fragility and joint hypermobility.
VASCULAR TYPE:
• It is due to defects in type III collagen.
• It is the most serious form of EDS.
• It is associated with potentially lethal arterial rupture.

27. Osteogenesis Imperfecta:
• This syndrome, known as brittle bone disease , is a genetic disorder of bone
fragility characterized by bones that fracture easily, with minor or no trauma.
• It is inherited as a dominant trait.
• It results due to mutation, which results in the replacement of single glycine
residue by cysteine in Type I collagen.
• Over 100 different types of mutations in the gene are reported.

28. • This change disrupts the triple helix near the carboxy terminal, So the
polypeptide becomes excessively glycosylated and hydroxylated.
• This leads to unfolding of helix and fibrillar array cannot be formed.
• Which results in brittle bones leading to multiple fractures and skeletal
deformities.

29. TYPES:
TYPE I OSTEOGENESIS IMPERFECTA:
• It is the most common form.
• It is characterized by mild bone fragility, hearing loss , and blue sclerae.
TYPE II OSTEOGENESIS IMPERFECTA:
• It is the most severe form.
• It is typically lethal in the perinatal period as a result of pulmonary
complications .
• In utero fractures are seen.

30. TYPE III OSTEOGENESIS IMPERFECTA:
• It is also a severe form.
• It is characterized by multiple fractures at birth, short stature ,
spinal curvature leading to a “humped-back”(kyphotic)
appearance and blue sclerae.
DENTINOGENESIS IMPERFECTA:
• It is a disorder of tooth development which may be seen in OI.

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