Fibrous Proteins and Collagen

• Fibrous proteins, including collagen, elastin, keratin, and fibroin, are structural elements.
• Fibrous proteins generally are insoluble, and are found only in animals
• Fibrous proteins are key components of skin, connective tissue, blood vessels, and the eye covering

Collagen

• Collagen is the most abundant protein in the human body, accounting for 25-35% of total body protein.
• It is a glycoprotein that contains galactose and glucose
• Collagen molecules exhibit a long, rigid structure consisting of three polypeptides (alpha chains) twisted together into a rope-like triple helix.
• Collagen can be bundled into tight, parallel fibers for strength or dispersed as a gel for structural support
• There are more than twenty-five types of collagen
• Types I, II, and III form rope-like structures
• Types IV and VII form a three-dimensional mesh
• Types IX and XII link collagen fibrils to each other and other extracellular matrix components.
• Collagen's structure is defined by a triple-helical arrangement with amino acid side chains located on the molecule's surface.
• It is rich in proline and glycine, which are important in forming the triple-stranded helix.
• Proline facilitates helix formation, thanks to its ring structure that causes 'kinks' in the peptide chain.
• Glycine is in every third position of the polypeptide chain
• The amino acid sequence is defined by Gly-X-Y
• X is frequently proline and Y is hydroxylysine or hydroxy lysine
• The hydroxyl group of hydroxylysine residues may be enzymatically glycosylated.
• Glucose and galactose are commonly attached to the polypeptide chain prior to triple helix formation.
• Collagen contains hydroxyproline (hyp) and hydroxylysine (hyl), which are not found in most other proteins

Collagen Biosynthesis

• Polypeptide precursors of collagen are synthesized in fibroblasts then secreted into the extracellular matrix
• The biosynthesis follows these steps:
  • Formation of pro-α chains in the RER
  • Hydroxylation in the ER cisternae requiring O2, Fe2+, and vitamin C
  • Glycosylation in the ER
  • Assembly and coiling in the Golgi apparatus
  • Extracellular cleavage of Procollagen molecules
  • Formation of collagen fibrils
  • Cross-link formation
• Hydroxylase enzymes in the ER cisternae add hydroxyl groups to some prolines and lysines requiring O2, Fe2+, and Vitamin C

Collagen Degradation

• Normal collagens are highly stable with half-lives that can be several years.
• Degradation of fibers is dependent on collagenases, found in the matrix metalloproteinases family

Collagenopathies

• Scurvy is a disease caused by vitamin C deficiency, impairing interchain H-bond formation and cross-linking of collagen fibrils.
• Results in easy bruising
• Ehlers-Danlos Syndrome (EDS) is a group of connective tissue disorders with defects in fibrillar collagen metabolism.
• The classic form of EDS causes skin extensibility and joint hypermobility
• Osteogenesis Imperfecta (OI) is a group of inherited disorders also known as brittle bone syndrome
• OI is often caused by mutations in the gene for type I collagen, leading to bones that easily bend and fracture

Elastin

• Elastin, a connective tissue protein, has rubber-like properties.
• Elastic fibers, composed of elastin and glycoprotein microfibrils, are found in lungs, large arteries, and elastic ligaments.
• Elastin can stretch several times its normal length and recoil to its original shape, consisting of tropoelastin.
• It is rich in proline and lysine but has only small amounts of hydroxyproline and hydroxylysine.
• Tropoelastin, secreted into the extracellular space, interacts with glycoprotein microfibrils like fibrillin to form elastin
• Lysyl oxidase then forms allysine residues from the lysyl side chains of tropoelastin polypeptides.
• Desmosine cross-links connect three allysyl side chains plus one unaltered lysyl side chain from the same or neighboring polypeptides.
• Mutations in the fibrillin gene can cause Marfan Syndrome

α₁-Antitrypsin in Elastin Degradation

• α₁-Antitrypsin inhibits neutrophil elastase, which degrades elastin in alveolar walls.
• Genetic defects in α₁-antitrypsin (AAT) can lead to emphysema and cirrhosis.
• A single purine base mutation (GAG-AAG) in the α₁ antitrypsin gene causes a substitution of lysine for glutamic acid at position 342, is the most widespread

α₁-Antitrypsin Role in Lungs

• In lungs, degenerating neutrophils normally degrade elastase by activation of AAT
• Methionine 358 in α₁-antitrypsin is essential for binding to target proteases.
• Smoking causes oxidation of methionine residue, rendering the inhibitor powerless to neutralize elastase.