collagen

• • collagen is the most abundant protein in the human body; 25% of total cellular protein is collagen
  • major component of the extracellular matrix (ECM)
  • 15 different types of collagen
  • ˜ 90% of collagen in the human body is type I, type II or type III collagen
  • fibrillar collagens
  • gram for gram, type I collagen is stronger than steel
  • multiple genes for some collagen
• • at least 25 collagen chains have been identified, each encoded by a different gene -> they assemble into about 15 different types of collagen
  • fibril-forming
  • I: most connective tissue (most abundant)
  • II: cartilage and vitreous humor
  • III extensible connective tissue (eg. skin, lungs, blood vessels)
  • network-forming
  • IV: basal lamina
• function of collagen

  • primary function:
  • structural and biochemical support to the surrounding cells
  • makes up a large portion of the bones and cartilage (connective tissues)
  • other functions
  • cell signaling (due to ECM and signaling molecules)
  • wound healing, growth (cells moving in ECM)
  • differentiation
  • cell survival, adhesion
  • collagen degradation = wrinkles
• osteogenesis imperfecta (OI):

  • genetic
  • a skeletal disease characterized by unusually fragile bones that break easily
  • OI affects between 20,000 and 50,000 people in the US
  • due to a malfunction in the body's production of collagen
  • collagen is found in the connective tissues of the body and makes up a large portion of the bones and cartilage. it is the substance that holds the tissues together, providing strength and mass to the bones
  • one mutation in one gene is sufficient to cause this
  • different levels of severity based on number of affected genes
• OI signs:

  fragile bones - triangular shaped face - blue sclerae (whites of eyes) - hearing loss beginning in twenties - scoliosis - thin, smooth skin - loose joints - low muscle tone - brittle teeth
• • 7 types of OI
  • 2 important types:
  • types I and II
• type I OI

  • I (osteogenesis imperfecta tarda): normal stature, little or no deformity, blue sclerae, hearing loss. Presents in early infancy with multiple fractures
  • autosomal dominant (new mutations common)
  • 50% reduction in type I collagen synthesis
• type II OI

  • II (osteogenesis imperfecta congenita): lethal in perinatal period; minimal calvarial mineralization, beaded ribs, compressed femurs, long bone deformity, flattened vertebrae
  • autosomal dominant (new mutations; reccurence due to parental mosaicism)
  • autosomal recessive (rare)
  • structural alteration in type I collagen chains - overmodification
• biphosphonates in the treatment of OI

  • biphosphonates act by inactivating osteoclasts, the cells that break down bone tissue and thus inhibit bone resorption
  • osteoblasts not doing enough
  • three different clinical trials have shown significant improvements in bone mineral density of OI patients after treatment with oral or intravenous biphosphonates
• the compact structure of collagen molecules gives them a high tensile strength (cable like)

  • collagen makes the ECM strong
• structure of collagen

  • three collagen chains are coiled into a triple helix (also called a collagen helix), wherever the Gly-X-Y sequence occurs
  • X = proline (non-polar amino acid with irregular geometry - secondary amine) and Y = hydroxyproline
  • the cyclic structure of proline inhibits rotation of the chains, stabilizing collagen
  • in type I collagen: triple helical tropocollagen
  • 3 pro-polypeptide strains are joined by h-bonds
  • stabilized by interchain hydrogen bonding rather than intrachain hydrogen bonding
  • glycine's small size allows the formation of a tightly packed triple helix
• collagen biosynthesis

  • proline to hydroxyproline is generated as the pre-propeptide is translocated to the ER
  • chains start folding in the ER
  • disulfide bonds form in the ER
  • can't in the cytosol
  • collagen molecules made of 3 a-chains which are assembled as procollagen in the ER
  • modified in the golgi and secreted to the extracellular space
  • cleavage of pro-peptides by proteinases
  • self-assembly due to hydrophobic, electrostatic and cross-linking interactions
  • 5 collagen molecules form a fibril, which associate into fibers
• • collagen self assembles into high order fibril structure in the ECM. 5 collagens align into stable fibrils through cross linking of the triple helices
  • collagen is maintained as procollagen until it is in the ECM, preventing fibril formation inside the cell
  • three chains assemble (ascorbate) -> procollagen peptidase (ADAMTS2) -> assembly (Cu 2+, lysyl oxidase) -> assembly -> collagen fiber
• hydroxylation of proline stabilizes the triple helix

  • Cγ-endo proline
  • the endo is the preferred conformation for proline sidechains in the X position of Gly-X-Y
  • Cγ-exo 4-hydroxyproline
  • the exo is the preferred conformation for proline sidechains in the Y position of Gly-X-Y
  • gly-endo-exo
  • twisty
  • hydroxylation of proline is a post translational modification
  • the hydroxyl group increases the thermal stability of the triple helix
• 4-prolyl-hydroxylase is the enzyme that adds the hydroxyl group to the proline

  • vitamin c is a cofactor
• scurvy

  • a collagen disease that results from a deficiency of vitamin C (ascorbate)
  • symptoms:
  • general weakness
  • spongy and bleeding gums
  • anemia
  • corkscrew hairs
  • perifollicular hemorrhage; follicular hyperkeratosis
• ehlers-danlos syndrome

  • one form is a deficiency in procollagen peptidase (ADAMTS2 gene)
  • symptoms:
  • loose joints
  • hyperextensible skin
  • several types
  • what doesn't occur if we have a defect in the procollagen peptidase? -> fibril formation doesn't occur
• menkes syndrome

  • defects in copper metabolism
  • symptoms:
  • kinky, steel colored hair (tyrosinase), connective tissue defects (lysyl oxidase) and neural/behavioral defects
  • lysyl oxidase crosslinks the collagen into fibrils in a copper dependent reaction
• • sequence variants in the gene that codes for the alpha 1 chain of type V collagen (COL5A1) has been linked to modest but statistically significant higher risk of tendon and ligament injuries in females
  • allelic variants in gene that codes for alpha 1 chain of type XII collagen (COL12A1) are associated with higher risk for ACL injuries
• elastin

  • a highly hydrophobic protein right in glycine and proline. a repeating peptapeptide Val-Pro-Gly-Val-Gly gives elastin its characteristic properties
  • secondary structure is a random coil that can stretch and relax. unique cross-links (desmosine and isodesmosine) function to return elastin to its original conformatioin
• marfan's syndrome

  • elastic fibrils are covered with microfibrils composed primarily of the glycoprotein fibrillin. mutations in the fibrillin gene result in marfan's syndrome
  • defect in the fibrillin protein, which binds to elastin and transforming growth factor-beta (TGF-beta)
  • marfan's patients normally have long slender limbs, dislocated lenses and aortic root dilation
  • the most serious complications of this disease include aortic aneurysm and aortic dissection
  • relatively common
• degradation of elastin in emphysema

  • α1-antitrypsin (also called α1-protease inhibitor) is a serum protein that controls the activity of neutrophil elastase
  • neutrophils are a part of your immune response. often many of the symptoms of a cold or flu are a result of our immune system making us feel sick in order to eradicate the virus (fever, etc)