Amino acids in formation of collagen
Collagen contains specific amino acids – Glycine, Proline, Hydroxyproline and Arginine. These amino acids have a regular arrangement in each of the three chains of these collagen subunits.
The sequence often follows the pattern Gly-Pro-X or Gly-X-Hyp, where X may be any of various other amino acid residues.
Proline or hydroxyproline constitute about 1/6 of the total sequence. Glycine (Gly) is found at almost every third residue. Glycine accounts for 1/3 of the sequence meaning that approximately half of the collagen sequence is not glycine, proline or hydroxyproline. Proline (Pro) makes up about 17% of collagen.
Collagen also has two uncommon derivative amino acids that are not directly inserted during translation. These amino acids are found at specific locations relative to glycine and are modified post-translationally by different enzymes, both of which require vitamin C as a cofactor.
Hydroxyproline is derived from proline and Hydroxylysine derived from lysine. Depending on the type of collagen, varying numbers of hydroxylysines are glycosylated (mostly having disaccharides attached).
In addition, the regular repetition and high glycine content is found in only a few other fibrous proteins, such as silk fibroin. In silk 75-80% is -Gly-Ala-Gly-Ala- with 10% serine, and elastin is rich in glycine, proline, and alanine (Ala), whose side group is a small, inert methyl group.
High glycine contents are not found in globular proteins except in very short sections of their sequence. Because glycine is the smallest amino acid with no side chain, it plays a unique role in fibrous structural proteins. Cortisol stimulates degradation of (skin) collagen into amino acids.
Formation of Type I collagen
Type I collagen is the most abundant collagen in the body.
Within the cell
- During translation, two types of peptide chains are formed on ribosomes along the rough endoplasmic reticulum (RER). These are called the alpha-1 and alpha-2 chains. These peptide chains (known as preprocollagen) have registration peptides on each end and a signal peptide.
- The preprocollagen is then released into the lumen of the RER. Thereafter the signal peptides are cleaved inside the RER and the peptide chains are now called pro-alpha chains.
- Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on ascorbic acid (Vitamin C) as a cofactor. Further glycosylation of specific hydroxylysine residues occurs.
- Triple helical structure is formed inside the endoplasmic reticulum from each two alpha-1 chains and one alpha-2 chain. This is called procollagen.
- Procollagen is transported into the golgi apparatus, where it is packaged and secreted by exocytosis.
Outside the cell
- Once outside the cell, the registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
- These tropocollagen molecules gather to form collagen fibrils, via covalent cross-linking by lysyl oxidase which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers.
- Collagen may be attached to cell membranes via several types of protein, including fibronectin and integrin.
Disorders of collagen synthesis
As is evident from the steps of collagen synthesis, Vitamin C forms an important component of the process. Vitamin C deficiency causes scurvy, a serious and painful disease in which the collagen that is synthesized is defective and it does not produce strong connective tissues. This leads to bleeding and peeling gums, loss of teeth, skin discoloration and non-healing wounds.
Prior to the eighteenth century, this condition was notorious among long duration naval and military expeditions during which participants were deprived of foods containing Vitamin C.
In addition, certain autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis may occur where the body’s immune system perceives the collagen as foreign and attacks and degrades the collgen in the body. Some bacteria and viruses also destroy collagen fibers in the body or interfere with its production.
Further Reading
Study suggests iron accumulation plays a central role in senescence and fibrosis