Extracellular matrix and GAGS

EXTRACELLULAR MATRIX
Muti ullah
Services institute of medical sciences

 Muti ullah
 Services institute of medical sciences
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.

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.
 Muti ullah
 Services institute of
medical sciences

 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.
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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.
 Muti ullah

CLASSIFICATION OF COLLAGEN:
FACITs = fibril-associated collagens with interrupted
triple helices. Muti ullah

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.
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2. Network Forming Collagens :
 Types IV andVIII 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 .
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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.
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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.
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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.
 Muti ullah

 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 andY can be any other amino acids, about
100 of the X positions are proline and about 100 of
theY positions are hydroxyproline. Muti ullah

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.

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.

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 .

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.

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 theY-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.

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

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.

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 .

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.

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.

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 .

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.

CLASSICTYPE:
 It is due to defect in collagen typeV.
 It is characterized by skin extensibility, skin fragility and joint hypermobility.
VASCULARTYPE:
 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.

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 inType I collagen.
 Over 100 different types of mutations in the gene are reported.

 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.

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.

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.

Extracellular matrix and GAGS

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Extracellular matrix and GAGS