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EXTRACELLULAR MATRIX
# (ECM)
## Ferbian Milas Siswanto, S.KH., M.Sc., Ph.D.
## Departemen Kimia dan Biokimia
## FKIK - UNIKA ATMA JAYA EXTRACELLULAR MATRIX ( ECM )
The extracellular matrix (ECM)
is a non -cellular three -dimensional
macromolecular network
composed of an array of
multidomain macromolecules
organized in a cell/tissue -specific
manner .
Component : structural protein
(collagen, elastin), specialized
protein (fibrillin, fibronectin,
laminin), proteoglycan
(glycosaminoglycans) .FUNCTIONS OF ECM
1. Mechanical support for cell anchorage and cell migration, and maintenance of cell polarity .
2. Control of cell growth, ECM components can regulate cell proliferation by signaling through cellular receptors
of the integrin family .
3. Maintenance of cell differentiation, morphogenesis, and homeostasis .
4. Scaffolding for tissue renewal . The integrity of the basement membrane or the stroma of the parenchymal cells
is critical for the regeneration of the tissues .COMPONENTS OF ECM
The ECM is a dynamic, constantly remodeling macromolecules complex synthesis, and secreted locally, which
assembles into a network in the spaces surrounding cells . The ECM is component of three groups of macromolecules :
1. Fibrous structural proteins, such as the collagens and elastin that provide tensile strength & recoil .
2. Adhesive glycoproteins, such as fibronectin and laminin, that connect the matrix elements to one another and to cells
3. Water hydrated gels such as proteoglycans and hyaluronic acid that provide resilience and lubrication .COLLAGEN
The collagens are a family of proteins that comprise
about 30% of total protein mass in the body and are
found to varying degrees in all tissues and organs.
To date, more than 30 types of collagens have been
identified that are broadly subclassified by their
function, domain structure, and supramolecular
organization.
The collagen family can be generally divided into
fibril -forming collagens (fibrillar) and nonfibrillar
collagens.
Collagen fibers are the most abundant structural
components of the ECM.
Type I collagen composition: [ 1(I)] 2 2(I) TYPES OF COLLAGEN (I) TYPES OF COLLAGEN (2) Tropocollagen
Covalent
crosslink
Extension peptides 20 to 35 kDa
procollagen aminoproteinase procollagen
carboxyproteinase Lysyl oxidase
(nonenzymatic) Glycation of collagen in the ECM increases the cross -linking of collagen.
>
The end -product of glycation reactions are termed AGEs (Advanced
Glycation End Products)
>
Cross -linking can lead to the accumulation of various plasma proteins in
the walls of blood vessels, in particular accumulation of LDL that can
contribute to atherogenesis.
>
Uptake of AGEs by endothelial cells and macrophages can activate the
transcription factor NF -kB, generating a variety of cytokines and pro -
inflammatory molecules. i. Affected individuals produce only 50% of the normal
amount of type I collagen, produced by the normal
allele
ii. Mechanisms
a) Splicing in 1 gene
b) Null mutation in 1 gene
# OSTEOGENESIS IMPERFECTA NONFIBRILLAR COLLAGENS
Nonfibrillar collagens
are a heterogeneous
group containing
triple -helical
segments of variable
length, interrupted
by one or more
intervening
nonhelical
segments.
Major type Type IV collagen = assembles into a flexible mesh -like network in basement
membranes.
Composition: 1(IV) [ 2(IV)] 2
Anomalies in type IV collagen in the kidney basement membrane result in glomerular diseases,
including Goodpastures syndrome . This is a rare autoimmune disease caused by the production
of antibodies that specifically bind to type IV collagen of basement membranes. Non -collagenous Proteins : ELASTIN
Elastin is a connective tissue protein responsible for
extensibility properties and elastic recoi l in tissues.
Distribution: lung, large arterial blood vessels, elastic
ligaments, skin, etc.
In contrast to collagen, only one genetic type of elastin is
known (ELN gene), although variants arise by alternative
splicing (13 variant).
Elastin is synthesized as a soluble monomer of ~70 kDa
called tropoelastin .
Some of the prolines of tropoelastin are hydroxylated to
hydroxyproline by prolyl hydroxylase DISEASES RELATED TO ELASTIN
>
Emphysema , due to elastase ( a protease with specificity for small
hydrophobic residues, such as alanine and valine) digests elastin in
the alveolar wall. FIBRILLIN
Microfibrils are fine fiber -like strands 10 to 12 nm in diameter which provide a scaffold for the
deposition of elastin in the ECM.
Fibrillins are large glycoproteins (about 350 kDa ) that are major structura l component of
these fibers.
They are secrete d (subsequent to a proteolytic cleavage) into the ECM by fibrob lasts and
become incorporated into the insolub le microfibrils.
Fibrillin -1 is the main fibri ll in present.
Other proteins inclu ding microfibril -associated glycoproteins (MAGPs) , fibulins , and
members of the ADAMTS family are also associated with microfibrils.
Fibri ll in microfibrils are found in elastic fibers and also in elastin -free bundles in the eye,
kidney, and tendons. FIBRONECTIN
Fibronectin is a major glycoprotein of the ECM, also foun d in a soluble form in plasma.
It consists of two identical subunits, each of about 230 kDa , joine d by two disu lfide bridges near their
C-terminals.
Humans have only one FN gene but are subject to considerab le alternative splicing (20 transcripts).
Fibronectin contains three types of repeating motifs (I, II, and III), which are organized into functional
domains (at least seven); functions of these domains inclu de binding fibronectin, fibrin, collagen, and
cell surfaces.
The binding to cell surface receptors of the integrin type is mediated by the sequence Arg -Gly -Asp
(RGD).
Many malignant cells are devoid of surface -bound FN, although they possess FN receptors. The
binding of these receptors to tissue FN facilitates metastasis. LAMININ
Laminins are a family of noncollagenous glycoproteins found in basement
membranes.
They are large (850 kDa ) heterotrimeric molecules composed of , , and
chains.
To date, five , four , and three chains have been identified, which can
associate to produce at least 15 different laminin variants.
The three interacting chains in a heterotrimer are arranged in an asymmetric
cruciform, or cross -shaped, molecule, held together by disulfide linkages.
Like fibronectin, laminins interact with cells through multiple binding sites in
several domains of the molecule.
Laminin polymers are also connected to type IV collagen by a single chain
protein ( nidogen/entactin ), which has a binding site for collagen, the heparan
sulfate proteoglycan ( perlecan ), and also has an RGD sequence for integrin
binding.
Nidogen plays a central role in the formation of crosslinks between laminin
and type IV collagen, generating a scaffold for anchoring of cells and ECM
molecules in the basement membrane. Structure of the basal
lamina . Laminin is attached
to type IV collagen via
nidogen and perlecan
(forming the basal lamina)
and to the epithelial cell layer
via integrins and
dystroglycan .PROTEOGLYCAN
Proteoglycans are the gel -forming components of the ECM
composed of core proteins containing covalently bound sugars
(glycosaminoglycans [GAGs]) and these units form large
complexes with other components of the ECM, such as
hyaluronic acid or collagen. STRUCTURE OF GLYCOSAMINOGLYCANS
GAGs are linear, unbranched oligosaccharides that may contain more than
100 sugar residues in a linear chain.
GAGs have a disaccharide repeat which is different for each type of GAG
but is usually composed of a hexosamine and a uronic acid residue, except
in the case of keratan sulfate, in which the uronic acid is replaced by
galactose.
The amino sugar in GAGs is either glucosamine (GlcNH2) or
galactosamine (GalNH2), both of which are present mostly in their N-
acetylated forms ( GlcNAc and GalNAc ).
In some of the GAGs (e.g., heparin, heparan sulfate), the amino group is
sulfated rather than acetylated.
The uronic acid is usually D-glucuronic acid ( GlcUA ), but in some cases
(e.g., dermatan sulfate, heparin), it may be L-iduronic acid ( IdUA ).
With the exception of hyaluronic acid and keratan sulfate, all the GAGs are
attached to protein by a core trisaccharide, Gal -Gal -Xyl ; the xylose is linked
to a serine or threonine residue of the core protein.
Keratan sulfate is also attached to protein, but in that case, the linkage is
through either an N-linked oligosaccharide (keratan sulfate I) or an O-linked
oligosaccharide (keratan sulfate II).
Hyaluronic acid, which has the longest polysaccharide chains, is the only
GAG that is not attached to a core protein. FUNCTIONS OF THE PROTEOGLYCANS
One of the major roles of proteoglycans is to provide
structural support to tissues, especially cartilage and
connective tissue.
In cartilage, large aggregates, composed of
chondroitin sulfate and keratan sulfate chains linked
to their core proteins, are noncovalently associated
with hyaluronic acid via link proteins, forming a jelly -
like matrix in which the collagen fibers are embedded.
This macromolecule, a bottlebrush structure
known as aggrecan, provides both rigidity and
stability to connective tissue SYNTHESIS OF
PROTEOGLYCANS DEGRADATION OF
## PROTEOGLYCANS
Lysosome
s
Protein portion lysosomal
proteases
GAG chains lysosomal
hydrolases THANK YOU
Ferbian Milas Siswanto, S.KH., M.Sc., Ph.D.
Departemen Biokimia , FKIK -Unika Atma Jaya
Email:
[email protected]
WA: 081337321736