Makindo Medical Notes

About

• Collagen is the most abundant protein in the human body, providing structural support to various tissues, including skin, bone, cartilage, and blood vessels.
• It is composed of 3 long polypeptide alpha chains (not 4), which twist together to form a triple helix structure that contributes to its strength and stability.
• Collagen is rich in amino acids such as glycine, hydroxyproline, and hydroxylysine, which play a crucial role in its structure and function.
• Proline hydroxylation, an important post-translational modification, is dependent on Vitamin C. A deficiency in Vitamin C leads to scurvy, resulting in weakened collagen fibers and poor wound healing.
• Matrix metalloproteinases (MMPs) are enzymes responsible for breaking down collagen during tissue remodeling and repair processes.
• Type IV collagen is a key component of basement membranes, providing structural integrity to tissues like the glomerulus in the kidney and the lens of the eye.
• Patients with osteogenesis imperfecta have defects in Type I collagen, leading to brittle bones and frequent fractures.
• Collagen has exceptionally high tensile strength, which allows tissues to resist stretching and maintain their structural integrity.
• The most common collagen defect in Ehlers-Danlos syndrome is in Type III collagen, which is primarily found in arteries and other blood vessels, contributing to vascular fragility.
• Ehlers-Danlos syndrome can also arise from defects in collagen-processing enzymes, such as lysyl hydroxylase or procollagen peptidase, leading to abnormal collagen formation and decreased tissue strength.

Types of Collagen

SCAB mnemonic:

• Skeleton - Type I
• Cartilage - Type II
• Arteries - Type III
• Basement membrane - Type IV

Collagen Synthesis

1. Translation (Preprocollagen Formation):
   • Collagen α-chains (preprocollagen) are synthesized in the rough endoplasmic reticulum (RER).
   • The sequence of collagen is usually Gly-X-Y, where:
     • X is often proline or lysine.
     • Y is often hydroxyproline or hydroxylysine.
   • Collagen is approximately 1/3 glycine, which remains constant compared to the variable content of lysine and proline.
2. Hydroxylation:
   • Specific proline and lysine residues are hydroxylated, a process dependent on Vitamin C.
   • Vitamin C deficiency leads to defective collagen hydroxylation, causing scurvy, characterized by weakened connective tissues.
3. Glycosylation:
   • Hydroxylated pro-α chains are glycosylated at specific hydroxylysine residues.
   • These chains form procollagen through hydrogen and disulfide bonds, creating a triple helix of 3 collagen α chains.
   • Problems in forming the triple helix lead to disorders such as osteogenesis imperfecta.
4. Exocytosis:
   • The procollagen is exocytosed from the cell into the extracellular space.
5. Proteolytic Processing:
   • Procollagen undergoes cleavage of its disulfide-rich terminal regions to form insoluble tropocollagen.
6. Assembly and Alignment:
   • Tropocollagen molecules assemble into fibrils and align in preparation for cross-linking.
7. Cross-linking:
   • Tropocollagen molecules are reinforced by covalent cross-linking between lysine and hydroxylysine residues, mediated by the copper-containing enzyme lysyl oxidase.
   • This cross-linking creates strong collagen fibers.
   • Cross-linking declines with age, contributing to tissue aging.
   • Problems with cross-linking, such as in Menkes disease, lead to weak collagen fibers.