The Extracellular Matrix (ECM)


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Introduction

The extracellular matrix (ECM) is a complex structural entity surrounding and supporting cells that are found within mammalian tissues. The ECM is often referred to as the connective tissue. The ECM is composed of 3 major classes of biomolecules:

1. Structural proteins: collagen and elastin.

2. Specialized proteins: e.g. fibrillin, fibronectin, and laminin.

3. Proteoglycans: these are composed of a protein core to which is attached long chains of repeating disaccharide units termed of glycosaminoglycans (GAGs) forming extremely complex high molecular weight components of the ECM. Proteoglycans are covered in the page on Glycosaminoglycans and Proteoglycans.

 

 

 

 

 

 

 

 

 

 

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Collagens

Collagens are the most abundant proteins found in the animal kingdom. It is the major protein comprising the ECM. There are at least 30 different collagen genes dispersed through the human genome. These 30 genes generate proteins that combine in a variety of ways to create over 28 different types of collagen fibrils. Types I, II and III are the most abundant and form fibrils of similar structure. Type IV collagen forms a two-dimensional reticulum and is a major component of the basal lamina. Collagens are predominantly synthesized by fibroblasts but epithelial cells also synthesize these proteins.

The fundamental higher order structure of collagens is a long and thin diameter rod-like protein. Type I collagen for instance is 300nm long, 1.5nm in diameter and consists of 3 coiled subunits composed of two α1(I) chains and one α2(I) chain. Each chain consists of 1050 amino acids wound around each other in a characteristic right-handed triple helix. There are 3 amino acids per turn of the helix and every third amino acid is a G. Collagens are also rich in proline and hydroxyproline. The bulky pyrollidone rings of proline reside on the outside of the triple helix.

Lateral interactions of triple helices of collagens result in the formation of fibrils roughly 50nm diameter. The packing of collagen is such that adjacent molecules are displaced approximately 1/4 of their length (67nm). This staggered array produces a striated effect that can be seen in the electron microscope.

Collagens are synthesized as longer precursor proteins called procollagens. Type I procollagen contains an additional 150 amino acids at the N-terminus and 250 at the C-terminus. These pro-domains are globular and form multiple intrachain disulfide bonds. The disulfides stabilize the proprotein allowing the triple helical section to form.

Collagen fibers begin to assemble in the ER and Golgi complexes. The signal sequence is removed and numerous modifications take place in the collagen chains. Specific proline residues are hydroxylated by prolyl 4-hydroxylase and prolyl 3-hydroxylase. Specific lysine residues also are hydroxylated by lysyl hydroxylase. Both prolyl hydraoxylases are absolutely dependent upon vitamin C as co-factor. Glycosylations of the O-linked type also occurs during Golgi transit. Following completion of processing the procollagens are secreted into the extracellular space where extracellular enzymes remove the pro-domains. The collagen molecules then polymerize to form collagen fibrils. Accompanying fibril formation is the oxidation of certain lysine residues by the extracellular enzyme lysyl oxidase forming reactive aldehydes. These reactive aldehydes form specific cross-links between two chains thereby, stabilizing the staggered array of the collagens in the fibril.

The Table below lists the characteristics of the 12 most characterized types of collagen fibrils. As indicated above there are at least 20 different types of collagen fibrils in the various ECMs of the body.

Types of Collagen

Type Chain Composition Gene Symbol(s) Structural Details Localization
I [α1(I)]2[α(I)] COL1A1, COL1A2 300nm, 67nm banded fibrils skin, tendon, bone, etc.
II [α1(II)]3 COL2A1 300nm, small 67nm fibrils cartilage, vitreous humor
III [α1(III)]3 COL3A1 300nm, small 67nm fibrils skin, muscle, frequently with type I
IV [α1(IV)2[α2(IV)] COL4A1 thru COL4A6 390nm C-term globular domain, nonfibrillar all basal lamina
V [α1(V)][α2(V)][α3(V)] COL5A1, COL5A2, COL5A3 390nm N-term globular domain, small fibers most interstitial tissue, assoc. with type I
VI [α1(VI)][α2(VI)][α3(VI)] COL6A1, COL6A2, COL6A3 150nm, N+C term. globular domains, microfibrils, 100nm banded fibrils most interstitial tissue, assoc. with type I
VII [α1(VII)]3 COL7A1 450nm, dimer epithelia
VIII [α1(VIII)]3 COL8A1, COL8A2   some endothelial cells
IX [α1(IX)][α2(IX)][α3(IX)] COL9A1, COL9A2, COL9A3 200nm, N-term. globular domain, bound proteoglycan cartilage, assoc. with type II
X [α1(X)]3 COL10A1 150nm, C-term. globular domain hypertrophic and mineralizing cartilage
XI [α1(XI)][α2(XI)][α3(XI)] COL11A1, COL11A2 300nm, small fibers cartilage
XII α1(XII) COL12A1   interacts with types I and III

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Clinical Significance of Collagen Disorders

Collagens are the most abundant proteins in the body. Alterations in collagen structure resulting from abnormal genes or abnormal processing of collagen proteins results in numerous diseases, e.g. Alport syndrome, Larsen syndrome, and numerous chondrodysplasias as well as the more commonly known clusters of related syndromes of osteogenesis imperfecta and Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome (EDS) is actually the name associated with at least ten distinct disorders that are biochemically and clinically distinct yet all manifest structural weakness in connective tissue as a result of defects in the structure of collagens. Osteogenesis imperfecta (OI) also encompasses more than one disorder. At least four biochemically and clinically distinguishable disorders have been identified and are identified as type I (mild), type II (perinatal lethal), type III (deforming), and type IV (mild deforming. All four forms are characterized by multiple fractures and resultant bone deformities.

Marfan syndrome (MFS) manifests itself as a disorder of the connective tissue and was believed to be the result of abnormal collagens. However, recent evidence has shown that MFS results from mutations in the extracellular protein, fibrillin, which is an integral constituent of the non-collagenous microfibrils of the extracellular matrix.

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Fibronectin

The role of fibronectins is to attach cells to a variety of extracellular matrices. Fibronectin attaches cells to all matrices except type IV that involves laminin as the adhesive molecule. Fibronectins are dimers of 2 similar peptides. Each chain is 60–70nm long and 2–3nm thick. At least 20 different fibronectin chains have been identified that arise by alternative RNA splicing of the primary transcript from a single fibronectin gene.

Fibronectins contain at least 6 tightly folded domains each with a high affinity for a different substrate such as heparan sulfate, collagen (separate domains for types I, II and III), fibrin and cell-surface receptors. The cell-surface receptor-binding domain contains a consensus amino acid sequence, RGDS.

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Laminin

All basal laminae contain a common set of proteins and GAGs. These are type IV collagen, heparan sulfate proteoglycans (HSPGs), entactin and laminin. The basal lamina is often refered to as the type IV matrix. Each of the components of the basal lamina is synthesized by the cells that rest upon it. Laminin anchors cell surfaces to the basal lamina.

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Representative matrix types produced by vertebrate cells

Collagen Anchor Proteoglycan Cell-Surface Receptor Cells
I fibronectin chondroitin and dermatan sulfates integrin fibroblasts
II fibronectin chondroitin sulfate integrin chondrocytes
III fibronectin heparan sulfate and heparin integrin quiescent hepatocytes, epithelial; assoc. fibroblasts
IV laminin heparan sulfate and heparin laminin receptors all epithelial cells, endothelial cells, regenerating hepatocytes
V fibronectin heparan sulfate and heparin integrin quiescent fibroblasts
VI fibronectin heparan sulfate integrin quiescent fibroblasts

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Michael W King, PhD | © 1996–2013 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org

Last modified: February 8, 2013