extracellular matrix and gags

EXTRACELLULAR MATRIX

Muti ullahServices institute of medical sciences

Muti ullahServices 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

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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.


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CLASSIFICATION OF COLLAGEN:

FACITs = fibril-associated collagens with interrupted triple helices.


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.


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 .


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.Muti ullahServices institute of medical sciences

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.Muti ullahServices institute of medical sciences

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 ullahServices institute of medical sciences

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.Muti ullah

Services institute of medical sciences

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 .

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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 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.

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 enzymesa. lysyl hydroxylaseb. N-procollagen peptidase2. Mutations in the amino acid sequences of collagen types I, III, or V.

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.

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.

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.

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