THE EXTRACELLULAR MATRIX

1. Structural proteins Collagen, elastin, and

fibrillin-1
2. Specialized proteins Fibronectin and laminin
3. Proteoglycans
COLLAGEN

Major component of connective tissue

25% protein of mammals
Provides extracellular framework
Collagen I&II the major collagen of skin, bone
tendon, blood vessels,conea, cartilage,
intervertebral disk and vitrious body.

FIBRONECTIN binds to aggregating

precollagen fibers and alters the kinetics of
fiber formation in the pericellar matrix.
TYPE IX COLLAGEN a minor collagen type
from cartilage contains an attached
glycosaminoglycan chain.
HEPATIC CIRRHOSIS may cause excessive
production of collagen.
Genetic
Disease
Ehlers-Danlos
Syndrome

Gene or
Enzyme
-Type IV
(most
serious)
-Lysyl
Hydroxylase
-Type VI
-Lysyl
Hydroxylase
Type VIIC
-Lysyl
Hydroxylase

S/Sx

Alport
Syndrome

Type IV
collagen
fibers-major
collagen
found in the
basement
membranes
of the renal
glomeruli
COL7A1/
Type VII
Colagen
Mutationin
keratin 5

HematuriaESR
D

Prolyl/Lysyl
hydroxylase
s

-Subcutaneous
haemorrhage
-bleeding gums
-poor wound
healing

COLLAGEN POST TRANSLATIONAL MODIFICATION

COLLAGEN MOST ABUNDANT PROTEIN

All collagen types have a TRIPLE HELICAL

STRUCTURE
GLYCINE residues occurs in the collagen at
every third position of the triple helical
portion of the alpha chain.
REPEATING STRUCTURE represented by the
(GLY-X-Y) is an absolute requirement for the
formation of triple helix.
PROLINE AND HYDROXYPROLINE confer
rigidity on the collagen molecule.
ASCORBIC ACID is the co-factor/co-enzyme of
PROLYL HYDROXYLASE formed
HYDROXYPROLINE by the organisational
hydroxylation of PEPTIDE bound residues.
Lysine in the Y position may also be post
translationally modified to hydroxylysine
through LYSYL HYDROXYLASE.
TYPE IV collagen the most important
component of basement membranes.
Collagen is synthesized PREPROCOLLAGEN
that contains a leader or signal sequence that
directs the polypeptide chain into the lumen
of the ER,
Both extension peptides contain CYSTEIN
residues. While the amino terminal
propeptide forms is only intrachain DISULFIDE
BONDS.
PROCOLLAGEN AMINO-PROTEINASE AND
PROCOLLAGEN CARBOXYPROTEINASE
removes the extension peptides at the amino
and carboxyl terminal end respectively.
Clevage of these propeptides may occur in
the CRYPTS or FOLDS in the CELL MEMBRANE.

EPIDERMOLYSIS
BULLUSA
EPIDERMOLYSIS
BULLUSA
Simplex
scurvy

Menkes disease

Copper
dependent
enzyme lysyl
oxidase

-Rupture of
arteries in the
bowel
-Ocular rupture
-joint
hypermobility
-soft skin

Skin breaks and

blisters as a
result of trauma

S/Sx = Lens dislocation (Ectopia Lentis), Tall

and Long digits(Arachnodactyly),
Hyperextensibility of joints, weakness of
aorta media-leading to dilation of ascending
aorta.
CAAUSE: mutation of (chromosome 5) for
Fibrillin 1
Cytokine TGF-B normally binds to fibrillin 1
The binding decrease due to low amount of
fibrillin 1

CONGENITAL CONTRACTURAL
ARACHNODACTYLY(Beals Syndrome)

Fibrillin 2 exist on chromosome 5; Gene

mutation.

FIBRONECTIN an important glycoprotein

involved in cell adhesions and migration.

ELASTIN

Connective tissue protein that is responsible

for properties of extensibility and elastic
recoil of tissues.
Synthesized as a soluble monomer of -70k
TROPOELASTIN
Lysyl residues of tropoelastin are oxidatively
deaminated to aldehydes by LYSYL OXIDASE.
The major cross-links formed in elastin are
the DESMOSINES, which result from the
condensation of three of these LYSINE
derived aldehydes with an unmodified lysine
to form tetrafunctional cross link unique to
elastin.

Major glycoprotein in ECM can be found in a

soluble form in plasma.
Consist of two identical subunits and joined
by two disulphide bridges near their carboxyl
terminals.
The INTEGRINS are heterodimers, containing
various types of a B-polypeptide chain.
Fibronectins ccontains ARG-GLYASP(RGD)sequence that binds to the
receptor.
The RGD sequence is shared by a number of
proteins present in the ECM that binds to
integrins present in cell surfaces
The fibronectin receptor interacts indirectly
with ACTIN microfilaments present in
CYTOSOL
The interaction of the fibrinogen to its
receptor provides one route whereby the
EXTERIOR OF THE CELL CAN COMMUNICATE
WITH THE INTERIOR and thus effects cell
behaviour.
Plays important role in CELL MIGRATION by
providing a binding site for cells and thus
helping them to steer their way through the
ECM.

LAMININ is a major protein component of renal

glomerular and other basal laminas

FEBRILLIN 1
Marfans Syndrome

Inherited disease affecting connective tissue;

imherited autosomal dominant trait.

Basal lamina-especialized areas of the ECM

that surrounds epithelial and some other cells
(e.g Muscle cells)
The primary components of of basal lamina
are three proteins-LAMININ, ENTACTIN, TYPE
IV Collagen, and the GAG heparin or
HEPARAN sulfate.
Consist of three distinct elongated
polypeptide polypeptide chains (a,b and y
chains).
ENTACTIN-nidogen a glycoprotein
containing an RDG sequence; binds to
laminin and is a MAJOR ATTACHMENT
FACTOR.
INULIN a small molecule which can pass
through glomerular membrane like water.
ALBUMIN is smaller than this pore size but is
prevented from passing through easily by
the NEGATIVE CHARGES of heparan sulfate

and of certain sialic acid-containing

glycoproteins present in the lamina.
GLUMERULONEPHRITIS alters the pores and
the amounts of the negatively charged
macromolecules and relatively massive
amounts of albumin (and certain plasma
proteins) can pass through into urine
resulting to severe ALBUMINURIA.

Keratan Sulfate
I

The GLYCOSAMINOGLYCANS found in

PROTEOGLYCANS are built up of repeating
disaccharides

PROTEOGLYCANS are proteins that

contain covalently linked
Glycosaminoglycans.
AGGRECAN-Major type of GAG found on
cartilage.
All GAGs contains sulfate group except
HYALURONIC ACID.

Biosynthesis of GLYCOSAMINOGLYCANS involves

attachment to CORE PROTEINS, CHAIN ELONGATION
and CHAIN TERMINATION

Keratan Sulfate
II

Attachment to core proteins- occurs in

ENDOPLASMIC RETICULUM; later steps occurs
in GOLGI APPARATUS.
1.
2.

3.

O-glycosydic bond between xylose and ser, a

bond that is unique to proteoglycans.
O-glycosidic bond forms between GalNAc (Nacetylgalactosamine) and ser (thr) present in
keratan sulfate II.
An N-glycosylamine bond between GlcNAc (Nacetylglucosamine) and the amide nitrogen
of Asn, as found in N-linked glycoproteins.

Heparin

Chain elongation

Appropriate nucleotide sugars and highly

specific Golgi-located Glycosyltransferases
are employed to synthesize the
oligosachharide of GAGs.

Heparan
Sulfate

Chain Terminatin
1.
2.

SULFATION particularly at certain position of

the sugars
Progression of the growing GAG chain away
from the membrane site where catalysis
occurs.

GAGs
HYALURONIC
ACID

CHONDROITIN
SULFATE

FUNCTION
>Unbranched
chain of
repeating
disaccharide
units
containing
GlcUA and
GlcNAc
> Joint support,
and combatting
osteoarthritis
>Facilitate cell
migration
>compressability
of cartilage
Important
component of

LOCATION
Present in
bacteria,
synovial fluid,
vitreous
humor, loose
connective
tissue.

Dermatan
Sulfate

Cartilage, bone
and Cornea

cartilage - the
tough connective
tissue that
cushions the
joints.
Consist of
repeating GalGlcNAc
disaccharide
units
containing
sulfate
attached to the
6 position of
GlcNAc or
occasionally
Gal.
>Corneal
Transparency
Consist of
repeating GalGlcNAc
disaccharide
units
containing
sulfate
attached to the
6 position of
GlcNAc or
occasionally
Gal.
The repeating
disaccharide
contains
glucosamine
(GlcN) and
either of the
uronic acids.
>Anticoagulant
Molecule that
is present on
many cell
surfaces as
proteoglycan
and is
extracellular.
>components
of plasma
membrane and
may act as
receptors and
participate in
cell adhesions
and cell-cell
interactions
>Charge
selectiveness
of renal
glomerulus
Components of
other vesicles.
Its structure is
similar with
that of
chondroitin
sulfate. Widely
distributed to
the animal

Cornea

Loose
connective
tissue

Mast cells

Skin fibroblast,
aortic wall

Wide
distribution

tissues.
>Structural
role in sclera
and in corneal
transparency.

GLYCOSAMINOGLYCA
NS

TISSUE DISTRIBUTION

Hyaluronic acid

Synovium, vitreous
humor

Chondroitin sulfate

Cartilage, bone, cornea

& heart valves

Heparan sulfate

Basement membrane

Heparin

Mast cell granules; lung,

liver & skin arteries

Dermatan sulfate

Skin, blood vessels &

heart valves

Keratan sulfate

Cornea, bone, cartilage

NICE TO KNOW