BIOCHEM 2.6 - EXTRACELLULAR MATRIX

• Extracellular matrix
• BMS 531 – FEBRUARY 17TH, 2025
• Recommended reading: Lippincott® Illustrated Reviews: Cell and Molecular Biology, 3e - Chapter 2

Learning Objectives

• Understand the general structure of the ECM and identify the macromolecules within the two important layers.
• Define the structure and function of key ECM components: laminin, non-fibrillar collagen, integrin, nidogen, perlecan, fibrillar collagen, fibronectin, elastin, and glycosaminoglycans.
• Explain the structure and function of hyaluronan and aggrecan, and identify their role in cartilage structure.
• Compare and contrast the different types of cellular junctions in terms of location, function, and important adhesion molecules.
• Recognize the clinical presentation of diseases associated with the ECM and cellular junctions, identifying the defective component.

Structure of the ECM

• The ECM consists of the Basement Membrane and the Interstitial Matrix

Basement Membrane (Basal Lamina)

• Composed of Laminin, Non-Fibrillar Collagen, Integrin, Nidogen, and Perlecan

Connective Tissue (Interstitial Matrix)

• Consists of Fibrillar Collagen, Fibronectin, Elastin, Hyaluronic Acid, and Proteoglycans

Laminins

• These are a large family of proteins.
• Each is composed of three polypeptide chains (α, β, and y).
• Disulfide bonds create the characteristic cross shape, enabling self-assembly into polymers in the presence of calcium.
• Structural differences based on cell type reflect varied ECM functions.
• Laminins create a scaffold for anchoring cells.

Clinical Correlation: Junctional Epidermolysis Bullosa (JEB)

• This condition features an Autosomal recessive inheritance.
• Implicated genes include LAMA3, LAMB3, and LAMC2.
• Complete loss of laminin function leads to a more severe phenotype.
• Patients present in infancy/childhood with blistering of the skin that heals with scarring.
• The prognosis is very poor and often fatal.

Non-Fibrillar Collagen

• This is composed of type IV collagen, featuring a triple helix structure held together by hydrogen bonds.
• Each chain consists of repeating units of glycine-proline-hydroxyproline.
• Hydroxylation of proline requires vitamin C.

Integrin, Nidogen, and Perlecan

• Integrins are components of hemidesmosomes, which are involved in linking a cell's epithelium to laminin within the basement membrane.
• Nidogen links with type IV collagen and laminin.
• Perlecan is a proteoglycan involved in crosslinking type IV collagen and laminin.

Fibrillar Collagen

• These are secreted by fibroblasts.
• They are composed of collagen types I, II, III, and V.
  • Type I is present bones, tendons, and ligaments.
  • Type II is present in cartilage and intervertebral discs.
  • Type III is present in skin and blood vessels.
• Fibroblasts secrete pro-peptides, which are then cleaved by peptidases to assemble into fibrils.
• They provide strength to connective tissue and aid in the formation of interchain crosslinks.

Clinical Correlation: Osteogenesis Imperfecta (OI)

• This condition features an autosomal dominant inheritance and is caused by mutations in genes COL1A1 and COL1A2.
• Mutations that change glycine to a different amino acid can affect type I collagen stability and fibril formation.
• Patients present at a young age with frequent fractures that may be misdiagnosed as child abuse.
• "brittle bone disease"

Elastin

• Found in the interstitial matrix/CT layer, it provides flexibility to the ECM, which is otherwise inelastic due to collagen.
• It is highly expressed in the lungs, blood vessels, and skin.
• Individual elastin molecules covalently cross-link to form elastin structure.
• Elastin is surrounded by fibrillin, which scaffolds for elastin deposition.
• It permits stretch and recoil of tissues subject to mechanical strain and deformation.

Clinical Correlation: Marfan Syndrome

• This has a Autosomal dominant inheritance.
• The implicated gene is FBN1.
• Mutations in fibrillin affect elastin fibril integrity, decreasing strength.
• Patients present with bone overgrowth, loose joints, abnormally long extremities and face, and may develop cardiovascular defects.
• Common condition.

Fibronectin

• This is present in the interstitial matrix/ CT layer.
• Fibronectin consists of polypeptide dimers that are linked at their C-terminus via disulfide bonds.
• Different binding regions attract various ECM and cellular proteins.
• The RGD region is responsible for integrin binding.
• Fibronectin attaches the basement membrane to connective tissue.
• It is also involved in cell migration.

Glycosaminoglycans (GAGS)

• GAGS features Covalently-linked repeating disaccharides
  • Sugar 1 includes Glucuronic/Iduronic acid OR galactose.
  • Sugar 2 includes N-acetylglucosamine OR N-acetylgalactosamine.
• It forms the gelatinous texture of the ECM.
• Examples:
• Hyaluronan, composed of glucuronic acid and N-acetylglucosamine, can withstand compressive forces.
• Aggrecan, composed of chondroitin and keratan sulfate assembles with hyaluronan to form large aggregates in cartilage.

Cell-Cell and Cell-ECM Adhesions

• These include Anchoring Junctions, Tight Junctions, and Gap Junctions.

Anchoring Junctions

• These connect cells to each other (cell-cell adhesions) or to the underlying ECM (cell-ECM adhesions).
  • Cell-cell adhesions include Adherens Junctions and Desmosomes.
  • Cell-ECM adhesions include Focal Adhesions and Hemidesmosomes.

Cell-Cell Adhesions

• Adherens Junctions form Cellular Adhesion Molecules (Cadherins):
  • E-cadherins, P-cadherins, and N-cadherins which is dependent on calcium for function.
  • It's Attaches to cytoskeleton via adapter proteins and attaches to actin filaments.
• Desmosomes attach to Desmosomal Cadherins and intermediate filaments.

Cell-ECM Adhesions

• Uses Integrins as Cellular Adhesion Molecule
• It attaches to either actin filaments (focal adhesions) or intermediate filaments (hemidesmosomes.)
• The function for both types of Cell adhesions are to determine shape, allows signaling, for force transmission, cell movement and rigidity

Clinical Correlation: Bullous Pemphigoid

• This is an autoimmune condition vs genetic.
• Autoantibodies generated against BP180/type XVII collagen and BP230 disrupt the normal structure of hemidesmosomes.
• The patient presents with severe blistering and inflammation.
• It can be countered with immunosuppressants (corticosteroids)

Tight Junctions and Gap Junctions

• Tight Junctions are Located towards the apical side of cells.
• They prevent unregulated vertical movement of molecules between cells and allow for movement of certain small molecules and ions (paracellular transport).
• Gap Junctions include connexins. Six subunits in one cell plus six more in another create a pore between adjacent cells.
• Gap Junction creates channels for movement of inorganic ions and water-soluble molecules between two cells.

Explore the structure and function of the extracellular matrix (ECM), including the basement membrane and interstitial matrix. Learn about key ECM components such as laminin, collagen, fibronectin, and glycosaminoglycans. Understand the structure of cellular junctions.