Collagen Flashcards
What tri-peptide is found as a regular repeat in fibril-forming collagens?
Gly-X-Y
X=proline
Y=hydroxyproline
Why does hydroxylation of proline stabilize the collagen helix?
Hydroxylation of proline fixes the side chain in the exo conformation, whicih is preferred for proline sidechains in the Y position –> increases collagen’s thermal stability & prevents unwinding
Why does collagen have such high tensile strength?
Multiple interchain hydrogen bonds and dense packing of the triple helix
Mutation of what residue in collagen would be most likely to cause disease and why?
Glycine
Any sidechain other than the hydrogen of Gly would disrupt packing in the collagen triple helix
Post translational modifications of collagen that occur inside the cell
Hydroxylation of Pro & Lys
Glycosylation of hydroxylysine
Disulfide bond formation at C-terminal propeptide extension
Why is vitamin C required for proper collagen fibril formation?
It’s required for prolyl and lysyl hydroxylation, which stabilizes the triple helix
What post-translational modifications of collagen occur after the molecule has been secreted?
Peptidases clip off N- and C-terminal extensions from the procollagen
Lysyl oxidation
Why do some modifications occur inside the cell and some outside?
Prevents the tropocollagen molecule from self-assembling inside the cell
Ehlers-Danlos syndrome
Deficiency in procollagen peptidase
–> carboxyl- and amino-terminal ends of procollagen aren’t cleaved into tropocollagen in the ECM, so fibrils don’t form
–> loose joints
Menke’s syndrome
Defect in copper (Cu) absorption or metabolism–> kinky, steel-colored hair, growth retardation, neural issues
Lysyl oxidase requires Cu2+ as a cofactor to crosslink collagen fibrils
Major collagen type in bones
Type I
Major collagen type in basement membranes
type IV
Why do disorders in type IV collagen cause hereditary nephritis?
Type IV collagen is the major scaffold protein of the basement membrane.
The double basement membrane in the glomerulus is responsible for keeping proteins in the plasma from spilling into the urine during glomerular filtration.
Increased degradation of elastin in the lung causes
emphysema
Fibrillin
Glycoprotein that coats elastin fibers
Marfan’s syndrome is a genetic disease that involves mutations in
The fibrillin gene
Elastin- what composition gives it its characteristic properties?
Highly hydrophobic protein rich in Gly and Pro; repeating peptapeptide Val-Pro-Gly-Val-Gly
Unique cross-links (desmosine & isodesmosine) allow it return to its original conformation
Secondary structure of elastin
Random coil that can stretch and relax
Elastic fibrisl are covered with
Microfibrils composed primarily of the glycoprotein fibrillin
a1-Antitrypsin
Produced primarily in the liver
Prevents elastin degradation by inhibiting elastase
A deficiency of a1-AT can cause
Emphysema and cirrhosis of the liver
(cigarette smoek can also stimulate elastase to lvls that can’ tbe controlled by a1-AT)
Big differences between Marfan’s and Homocystinuria
Fragile bones that break easily, triangular-shaped face, blue sclera, hearing loss, scoliosis, thin, smooth skin, loose joints, low muscle tone, brittle teeth
Type I Osteogenesis Imperfecta - AD mutation that reduces type I collagen by 50%
Type II OI
Type II is more severe, resulting in death during embryogenesis or by bone fracturing during birthing; results from a change in the modifications that occur to collagen during synthesis
Treatment of osteogenesis imperfecta
Bisphosphonates inactivates/causes apoptosis of osteoclasts (breaks down bone tissue) and decreases apoptosis among osteoblasts (lays down new bone)
Tropocollagen
The triple helix of type I collagen
Tendon vs skin
Collagen & elastin content
Tendon needs to be strong -> collagen
Skin needs to stretch -> elastin
Scurvy
Deficiency of vitamin C
–> proline-4-hydroxylase can’t convert Pro to 4-hydroxypro for the Y position in collagen
–> unstable collagen
–> weakness, spongy/bleeding gums, poor wound healing, follicular hyperkeratosis, perifollicular hemorrhage
Fibril collagens
Types 1, 2, 3, 5, 11
Characteristic tropocollagen tripl ehelix that forms staggered fibrils –> striation
Collagen synthesis
- Translation on RER into preprocollagen
- Translocation into the ER while proline 4-hydroxylase generates 4-hydroxyprolines at the Y position
- Cleave off signal sequence & form a triple helix in the cytosol into procollagen
- Disulfide bonds between carboxyl-terminal ends
- Secretion out into the ECM, where procollagen peptidases cleave the carboxyl-terminal and amino-termianl ends into collagen
Fibril-associated collagens
Interrupted triple helcies with globular heads on them
Sheet/network-like collagen
type 4 inthe basement membranes and basal lamina
Anchoring fibrils
type 7
Supports or connects dermal and epidermal layers
Alport’s syndrome
Disorders of basement membranes of kidney, cochlea, and eye due to mutations in type 4 collagen in basement membranes & basal lamina.
–> proteinuria, HTN, end-stage renal disease, hearing loss
X-linked or AD, depending on which type IV collagen gene is involved
