Harvey's Garden

Extracellular matrix

4 min read

  • Overview
    • Network of proteins and polysaccharides secreted by cells.
    • Provides structural support, regulates cell signaling, adhesion, migration, and proliferation.
    • Composed of:
      1. Structural Proteins (Collagen, Elastin)
      2. Adhesive Glycoproteins (Fibronectin, Laminin)
      3. Proteoglycans & Glycosaminoglycans (GAGs)

Structural Proteins

1. Collagen

Structure

  • A collagen molecule is a protein with a repeating amino acid sequence (Gly-X-Y)n.
    • The first amino acid of this triplet is glycine (collagen is comprised of ⅓ glycine).
    • Position X: most commonly proline (also common: lysine, hydroxylysine)
    • Position Y: most commonly hydroxyproline (also common: hydroxylysine, lysine)

Collagen Synthesis & Processing

  • 1. Synthesis (in RER):
    • Synthesis of preprocollagen (α-chains).
  • 2. Hydroxylation (in RER):
    • Hydroxylation of specific proline and lysine residues.
    • Requires prolyl hydroxylase and lysyl hydroxylase.
    • Cofactor: Vitamin C (ascorbic acid). Deficiency → Scurvy.
    • Purpose: To add hydroxyl (-OH) groups to proline and lysine. These groups are essential for forming the hydrogen bonds that stabilize the triple helix structure in the next step. Without hydroxylation, the helix is unstable.
  • 3. Glycosylation (in RER):
    • Glycosylation of hydroxylysine residues.
    • Formation of procollagen (triple helix) from 3 α-chains. Problems with triple helix formation → Osteogenesis Imperfecta.
    • Purpose: Glycosylation helps correctly align the three α-chains. The subsequent formation of the procollagen triple helix creates a stable, soluble, and transportable precursor molecule ready for secretion.
  • 4. Exocytosis (to Extracellular Space):
    • Procollagen is transported out of the cell.
  • 5. Proteolytic Processing (Extracellular):
    • Cleavage of disulfide-rich terminal regions of procollagen by procollagen peptidases.
    • Forms insoluble tropocollagen. Problems with cleavage → a form of Ehlers-Danlos Syndrome.
    • Purpose: To cleave the terminal propeptides, converting soluble procollagen into insoluble tropocollagen. This insolubility is crucial, as it allows the tropocollagen molecules to self-assemble into fibrils. The propeptides prevent this aggregation from happening inside the cell.
  • 6. Cross-linking (Extracellular):
    • Reinforcement of multiple tropocollagen molecules by covalent lysine-hydroxylysine cross-linkage.
    • Catalyzed by lysyl oxidase.
    • Cofactor: Copper (Cu²⁺). Deficiency or problems with lysyl oxidase → Ehlers-Danlos Syndrome, Menkes Disease.

Types

And scar tissue (late stages of wound healing, e.g. post-MI) See Osteogenesis imperfecta

Tip

  • Compare with ligaments, which are made of elastin.
  • Ligaments attach bone to bone, and tendons attach muscle to bone.
  • Connect presence of elastin with Marfan syndrome
    • FBN1 can disrupt the normal regulation of TGF-β → Tall stature
    • Skin → Skin hyperextensibility
    • Large arteries → aortic dilation, aneurysms, or dissection
    • Elastic ligaments → Joint hypermobility
    • Lung → Increased risk of spontaneous pneumothorax

Deficient in vascular type of Ehlers-Danlos syndrome (threE D).

See Goodpasture syndrome

2. Elastin

  • Function: Provides stretch and recoil to tissues.
  • Location: Skin, lungs, large arteries (aorta), elastic ligaments.
  • Structure: Rich in non-hydroxylated proline, glycine, and lysine.
  • Synthesis: Tropoelastin is secreted and cross-linked by lysyl oxidase (requires copper) to form elastin.
  • Key Associations:
    • Fibrillin-1 acts as a scaffold for elastin deposition. A defect in fibrillin-1 causes Marfan syndrome.
    • Elastin is broken down by elastase. Elastase is inhibited by α1-antitrypsin.
    • Deficiency of α1-antitrypsin → excessive elastase activity → destruction of elastic fibers in the lungs → emphysema.

Adhesive Glycoproteins

  • Function: Connect cells to the ECM.
  • Laminin:
    • Key component of the basement membrane.
    • Binds Type IV collagen, heparan sulfate, and integrins on the cell surface.
  • Fibronectin:
    • Binds integrins, collagen, and heparin.
    • Mediates cell adhesion and migration. Important in wound healing.

Proteoglycans & Glycosaminoglycans (GAGs)

  • Function: Form a hydrated, gel-like matrix that resists compressive forces. Binds growth factors.
  • Structure:
    • Proteoglycan: Core protein + covalently attached GAGs.
    • GAGs: Long, unbranched polysaccharides of repeating disaccharide units. Highly negatively charged (sulfate and carboxyl groups) which attracts Na⁺ and water, creating the gel-like consistency.
  • Major GAGs:
    • Hyaluronic acid (Hyaluronan): Unique. Not sulfated and not attached to a core protein. Found in synovial fluid, vitreous humor.
    • Chondroitin sulfate: Most abundant GAG. In cartilage, bone, tendons.
    • Heparan sulfate: In basement membrane, on cell surfaces.
    • Dermatan sulfate: Skin, blood vessels, heart valves.
    • Keratan sulfate: Cornea, cartilage.
  • Pathology:
    • Mucopolysaccharidoses (e.g., Hurler syndrome, Hunter syndrome) are lysosomal storage diseases caused by a deficiency of enzymes needed to degrade GAGs.

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