Flashcards in Lecture 23 Deck (23)
Collagens are the most _______ protein in the body
What are four characteristics of fibrous proteins (collagens and elastin)?
3) Long biological half-life
4) High tensile strength and contractibility, respectively
Where do elastins and collagens function?
Elastins and collagens function in extracellular space (matrix)
What are 3 types of collagens?
1) Fibril-forming (classic)
What are characteristics of the structure of collagen?
1) All collagens are triple-helically structured
2) They all have the amino acid structure Gly-X-Y (X is frequently proline; Y is frequently (hydroxy)-proline or (hydroxy)-lysine)
3) They are all rich in (hydroxy)-proline and (hydroxy)-lysine
What modification occurs to the collagen protein post-translationally?
1) Some proline residues are hydroxylated by prolylhydroxylase. Some lysine residues are hydroxylated by lysylhydroxylase
2) Some of these hydroxylated residues are further modified by glycosylation with glucose and galactose
3) Three pro-alpha-chains assemble and form disulfide bonds at the C-terminal propeptide extension. They use a zipper-like folding to form a triple helix
4) Procollagen molecule is secreted from a Golgi vacuole into the extracellular matrix
5) The N-terminal and C-terminal propeptides are cleaved by procollagen peptidases, allowing assembly of collagen into fibrils
1) Hydroxylation & Glycosylation
2) Chain association
5) Assembly into fibrils
In order to hydroxylate proline and lysine, what cofactors are required?
Iron 2+ ion and vitamin C
How does collagen structure stabilize its triple helix?
Collagen is cross-linked by lysyl oxidase. Lysyl oxidase requires copper as a cofactor to do so
What are two diseases that affect lysyl oxidase?
1) Menkes Disease
2) Wilson's Disease
What is Menkes disease?
Menkes disease is an X-linked recessive disorder that is the result of a mutation in the ATP7A gene. Copper is poorly distributed to cells in the body. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels. The lack of copper in certain areas disallows proper structure of collagen due to a lack of function of lysyl oxidase
What is Wilson's disease?
Wilson's disease or hepatolenticular degeneration is an autosomal recessive genetic disorder in which copper accumulates in tissues; this manifests as neurological or psychiatric symptoms and liver disease. The condition is due to mutations in the Wilson disease protein (ATP7B) gene
What is scurvy?
Scurvy is a non-genetically based collagen disorder resulting from a lack of Vitamin C. It results in easily bruised skin, bleeding gums, loosened teeth, "corkscrew hairs", & poor wound healing. Only common now in places of the world with malnutrition
Who conducted the first clinical trial, what was the disease being tested for, & what was the cure?
Dr. James Lind in 1747; Scurvy; Citrus fruit
What are two genetically-based collagen disorders?
Osteogenesis imperfecta (OI) & Ehlers-Danlos syndrome
Describe the types of Osteogenesis imperfecta (OI)
Type 1 - presents in infancy or early childhood (least severe)
Type 2 - Most severe; usually die in utero or shortly after
2>3>4>1 (in terms of severity)
What causes type 2, 3, and 4 of Osteogenesis imperfecta (OI)?
Mutations in type 2, 3, and 4 result from substitutions in the gene for COL1A1 or COL1A2 that result in the change from Gly to another amino acid with a bulky side chain
What is Dentiogenesis imperfecta (DI)?
Same concept as osteogenesis imperfecta (OI), but in the teeth. Lack of collagen in teeth
What causes type 1 Osteogenesis imperfecta (OI)?
Usually a splice site mutation that results in a decrease in the amount of collagen being made. However, the collagen that is made is perfectly functional, hence why type 1 is less debilitating
What is blue sclera caused by?
A thinner eye lens causes the underlying veins to be exposed more profusely
What is Ehlers-Danlos Syndrome (EDS)?
Ehlers–Danlos syndrome (EDS) is an inherited connective tissue disorder caused by a defect in the structure, production, or processing of collagen or proteins that interact with collagen, such as mutations in the COL5A or COL3A genes. Results in a collection of skin and joint hypermobility defects. Vascular (IV) causes uterine or arterial rupture (defect in COL3A1)
What are characteristics of elastin?
1) A rubbery, connective tissue protein
2) Can be stretched to several times normal length
3) Found in walls of large arteries, lungs, & elastic ligaments
4) insoluble protein polymer synthesized from precursor - tropoelastin
5) only one genetic type unlike collagen
6) rich in glycine, proline, and lysine (also has a bit of hydroxyproline, but no hydroxylysine)
7) Is secreted by cells into extracellular space
8) interacts with fibrillin in extracellular space
What is Marfan syndrome?
Marfan syndrome is an autosomal dominant disorder that has been linked to the FBN1 gene on chromosome 15. FBN1 encodes a protein called fibrillin, which is essential for the formation of elastic fibers found in connective tissue. Without the structural support provided by fibrillin, many tissues are weakened, which can have severe consequences. For example, ruptures in the walls of major arteries