Fibrous Proteins: Fibrous Proteins: CollagenCollagen

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Types of CollagenTypes of Collagen• The collagen super family of proteins includes more than 25

collagen (approximately 28) types, as well as additional proteins that have collagen-like domains.

• Variations in the amino acid sequence of the α chains result in structural components that are about the same size (approximately 1,000 amino acids long), but with slightly different properties.

Types of CollagenTypes of Collagen• These α chains are combined to form the various types of collagen

found in the tissues. For example, the most common collagen, type I, contains two chains called α1 and one chain called α2 (α12α2), whereas type II collagen contains three α1 chains (α13).

• The collagens can be organized into three groups, based on their location and functions in the body

Structure of collagen• Amino acid sequence:

• Collagen is rich in proline and glycine, both of which are important in the formation of the triple-stranded helix.

• Proline facilitates the formation of the helical conformation of each α chain because its ring structure causes “kinks” in the peptide chain.

Structure of collagen

• Glycine, the smallest amino acid, is found in every third position of the polypeptide chain. It fits into the restricted spaces where the three chains of the helix come together.

• The glycine residues are part of a repeating sequence, –Gly–X–Y–, where X is frequently proline and Y is often hydroxyproline (but can be hydroxylysine).

Triple-helical structure

• Unlike most globular proteins that are folded into compact structures, collagen has an elongated, triple-helical structure that places many of its amino acid side chains on the surface of the triple-helical molecule.

Hydroxyproline and Hydroxylysine

• Collagen contains hydroxyproline (hyp) and hydroxylysine (hyl), which are not present in most other proteins.

• These residues result from the hydroxylation of some of the proline and lysine residues after their incorporation into polypeptide chains (post translational modification)

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Glycosylation

• The hydroxyl group of the hydroxylysine residues of collagen may be enzymatically glycosylated.

• Most commonly, glucose and galactose are sequentially attached to the poly - peptide chain prior to triple-helix formation

Biosynthesis of collagen• The polypeptide precursors of the collagen molecule are

formed in fibroblasts (or in the related osteoblasts of bone and chondroblasts of cartilage), and are secreted into the extracellular matrix.

• After enzymic modification, the mature collagen monomers aggregate and become cross-linked to form collagen fibers.

Biosynthesis of collagen

Degradation of collagen• Normal collagens are highly stable molecules, having

half-lives asnlong as several years.

• However, connective tissue is dynamic and is constantly being remodeled, often in response to growth or injury of the tissue.

Degradation of collagen

• Breakdown of collagen fibers is dependent on the proteolytic action of collagenases, which are part of a large family of matrix metalloproteinases.

Collagen diseases:

Collagenopathies

Scurvy• A disease resulting from a deficiency of vitamin C, which

is required for the synthesis of collagen in humans.

• Scurvy often presents itself initially as symptoms of malaise and lethargy, followed by formation of spots on the skin, spongy gums, and bleeding from the mucous membranes.

Scurvy• In ascorbic acid deficiency (and, therefore, a lack of prolyl

and lysyl hydroxylation), interchain H-bond formation is impaired, as is formation of a stable triple helix.

• Additionally, collagen fibrils cannot be cross-linked (see below), greatly decreasing the tensile strength of the assembled fiber. Patients with scurvy also often show bruises on the limbs as a result of subcutaneous extravasation of blood due to capillary fragility

Ehlers-Danlos Syndrome (EDS)

• This disorder is a group of generalized connective tissue disorders that result from inheritable defects in the metabolism of fibrillar collagen molecules.

• It is a group of inherited disorders that affect your connective tissues — primarily your skin, joints and blood vessel walls. 

Ehlers-Danlos Syndrome (EDS)

• EDS can result from a deficiency of collagen-processing enzymes (for example, lysyl hydroxylase or procollagen peptidase), or from mutations in the amino acid sequences of collagen types I, III, or V.

Ehlers-Danlos Syndrome (EDS)

• The most clinically important mutations are found in the gene for type III collagen.

• Collagen containing mutant chains is not secreted, and is either degraded or accumulated to high levels in intracellular compartments.

• Because collagen type III is an important component of the arteries, potentially lethal vascular problems occur.

Osteogenesis Imperfecta (OI)

• This disease, known as brittle bone syndrome, is a group of inherited disorders distinguished by bones that easily bend and fracture.

• They are around eight (8) types of OI but type 1 is the most common

• Most patients with severe OI have mutations in the gene for either the pro-α1 or pro-α2 chains of type I collagen.

• The most common mutations cause the replacement of glycine residues (in –Gly–X–Y–) by amino acids with bulky side chains. The resultant structurally abnormal pro-α chains prevent the formation of the required triple-helical conformation.

• Type I OI is called osteogenesis imperfecta tarda. The disease is the consequence of decreased production of α1 and α2 chains.

• It presents in early infancy with fractures secondary to minor trauma, and may be suspected if prenatal ultrasound detects bowing or fractures of long bones.

• Type II OI is called osteogenesis imperfecta congenita, and is the most severe. Patients die of pulmonary hypoplasia in utero or during the neonatal period.

References and Appendix

Cowan, R., Gaw, A., Murphy, M., & O'Reilly, D. S. (2013). Clinical Biochemistry, 5th Edition. USA: Churchill Livingstone Elsevier.

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