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M03.04.08 Posttranslational Modifications of Collagen
Collagen is a structural protein that undergoes several essential co- and posttranslational modifications during its synthesis. These modifications are critical for collagen’s stability, functionality, and its role in the extracellular matrix. Collagen’s unique structure consists of a repeating tripeptide sequence, Gly-X-Y, where X and Y are often proline and hydroxyproline. The modification of collagen includes hydroxylation, glycosylation, and cross-linking, which are vital for its maturation and function.
Steps of Collagen Synthesis
- Synthesis of Pre pro-α Chains
- Ribosomes on the rough endoplasmic reticulum (RER) synthesize pre pro-α chains with a hydrophobic signal sequence.
- Formation of Pro-α Chains
- The hydrophobic signal sequence is cleaved by signal peptidase within the RER, forming pro-α chains.
- Hydroxylation of Prolines and Lysines
- Selected proline and Lysine residues are hydroxylated by prolyl and Lysyl hydroxylases, enzymes that require ascorbate (vitamin C) as a cofactor. This step is crucial for collagen stability, and a deficiency in vitamin C results in scurvy.
- Glycosylation of Hydroxylysines
- Some hydroxylysine residues undergo glycosylation, adding carbohydrate groups to the growing collagen molecule.
- Triple Helix Formation (Procollagen)
- Three pro-α chains align and form a triple helix known as procollagen, which is stabilized by hydrogen bonds.
- Transport to the Golgi Apparatus
- The procollagen is transferred to the Golgi apparatus, where further modification of oligosaccharides occurs.
- Secretion of Procollagen
- The modified procollagen is secreted into the extracellular space.
- Cleavage of Propeptides
- Extracellular proteases cleave the propeptides from the ends of the procollagen, forming mature collagen (tropocollagen).
- Fibril Formation
- Collagen molecules self-assemble into fibrils. Cross-linking between lysine residues occurs through the action of lysyl oxidase, an enzyme requiring copper and oxygen.
- Formation of Collagen Fibers
- The fibrils aggregate and cross-link to form collagen fibers, providing strength and stability to tissues.
Types of Collagen and Associated Diseases
| Type of Collagen | Characteristics | Tissue Distribution | Associated Diseases |
|---|---|---|---|
| I | High tensile strength | Bone, skin, tendons | Osteogenesis imperfecta, Ehlers-Danlos (various) |
| II | Thin fibrils, structural | Cartilage, vitreous humor | — |
| III | Pliable | Blood vessels, granulation tissue | Ehlers-Danlos (Type IV), Keloid formation |
| IV | Amorphous, structural support | Basement membranes | Goodpasture syndrome, Alport disease |
Disorders of Collagen Biosynthesis
| Disease | Defect | Major Symptoms |
|---|---|---|
| Scurvy | Deficient hydroxylation (Ascorbate deficiency) | Petechiae, ecchymoses, bleeding gums, poor wound healing |
| Osteogenesis Imperfecta | Mutations in collagen genes | Skeletal deformities, fractures, blue sclera |
| Ehlers-Danlos Syndrome | Mutations in collagen genes or hydroxylases | Hyperextensible skin, joint hypermobility, arterial ruptures |
| Menkes Disease | Deficient cross-linking (copper deficiency) | Steely hair, arterial tortuosity, cerebral degeneration |
Points to Remember
- Hydroxylation of proline and Lysine residues is a key step in collagen maturation, requiring vitamin C as a cofactor.
- Defective collagen synthesis leads to various diseases like scurvy, Osteogenesis imperfecta, and Ehlers-Danlos syndromes.
- Lysyl oxidase, an enzyme that requires copper, is crucial for collagen fibril cross-linking.
Bibliography
- Lodish, H., et al. (2016). Molecular Cell Biology. W.H. Freeman.
- Prockop, D.J., & Kivirikko, K.I. (1995). Collagens: Molecular Biology, Diseases, and Potentials for Therapy. Annual Review of Biochemistry, 64, 403-434.
- Shoulders, M.D., & Raines, R.T. (2009). Collagen Structure and Stability. Annual Review of Biochemistry, 78, 929-958.