Lecture 9 - Fibrillar proteins (extracellular matrix Flashcards
In order to remodel the matrix, the cells secrete these things that degrade the matrix proteins called what?
Matrix metalloproteinases (MMPs, Zn2+)
The activity Metalloproteinases (MMPs) is controlled by specific inhibitors called?
Tissue Inhibitors of MetalloProteinases (TIMPs)
These very frequently secrete large amounts of matrix
metalloproteinases (MMPs) to invade the surrounding tissue.
Cancer cells
Synthesis of procollagen chains occurs where?
Rough endoplasmic reticulum
The triple helix forms where?
Rough endoplasmic reticulum
The triple helix is stabilized by what?
Hydroxyproline and hydrogen bonds
Hydroxyproline is produced by what enzyme?
Prolyl hydroxylase.
Prolyl hydroxylase requires what cofactors ?
Fe2+ and Vitamin C (ascorbate)
Crosslinking of collagen chains is helped by what?
Hydroxylysine
Hydroxylysine is produced by what enzyme?
Lysyl hydroxylase
Lysyl hydroxylase requires what cofactors?
Fe2+ and Vitamin C (ascorbate)
The covalent crosslinks within collagen fibers are created through the formation of what?
Oxidized lysine and hydroxylysine residues
Oxidization of lysine and hydroxylysine is catalyzed by what enzyme?
Lysyl oxidase.
Lysyl oxidase requires what cofactor?
Cu2+
Collagen type?
skin, bone, tendon, blood vessels, cornea
Type 1
Collagen type?
cartilage, intervertebral disk, virteous body
Type 2
Collagen type?
Blood vessels, fetal skin
Type 3
Collagen type?
Basement membrane
Type 4
- Caused by lack of fruits and vegetables in the diet.
- Prolyl and lysyl hydroxylases are not efficient (require Vitamin C).
- The collagen triple helix is less stabile and crosslinking is also reduced.
- General connective tissue disease.
Vitamin C deficiency
Scurvy
Symptoms of what disease?
- Bruises on skin (especially on legs)
- Bleeding gums, loose teeth
- Delayed wound healing
- Bone and joint abnormalities (especially in infants)
Vitamin C deficiency
Scurvy
-Disease associated with Type I collagen mutations.
by either reduced number of collagen fibrils, or by defective collagen fibrils.
-Severity can range from perinatal lethal to mild predisposition to fractures
Osteogenesis Imperfecta (OI)
Symptoms of what disease?
- Increased incidence of fractures
- Short stature
- Grey or brown teeth that wear down easily (dentinogenesis imperfecta)
- Blue sclera
Osteogenesis Imperfecta (OI)
Disease mainly associated with hyperextensive skin, delayed wound healing, etc. Has various forms
Ehlers-Danlos syndrome (EDS)
Form of Ehlers-Danlos syndrome (EDS) -mutations in type V collagen (a fibril associated collagen) Symptoms: -hyperextensive skin -delayed wound healing, atrophic scars -joint hypermobility
Classic type
Form of Ehlers-Danlos syndrome (EDS)
-mutations in type III collagen
Symptoms:
-arterial, intestinal and uterine (during pregnancy) ruptures
Vascular type
Form of Ehlers-Danlos syndrome (EDS) -mutations in lysyl hydroxylase Symptoms: -hyperextensive skin -delayed wound healing, easy bruising, thin scars -joint hypermobility -progressive scoliosis (abnormal curving of the spine) -increased risk of vascular rupture
Kyphoscoliotic type
Disease caused by mutations in the Type IV collagen genes
-Affects glomerular basement membranes and can lead to renal failure.
Alport syndrome
Symptoms of what disease?
- Hematuria (appearance of red blood cells in urine)
- Proteinuria (increased protein in urine)
- Renal insufficiency
- Sensorineural hearing loss (mutation affects the basement membrane of the organ of Corti in the cochlea of the inner ear)
Alport syndrome
Disease where the lung will have lower elastin content, which can lead to the collapse of the small airways (alveoli) when the patient exhales, and leads to emphysema (manifests as shortness of breath).
α1-antitrypsin deficiency
What causes α1-antitrypsin deficiency
In the lung, elastin can be degraded by neutrophil elastase (a proteolytic enzyme). α1-antitrypsin, a natural inhibitor of this enzyme, is responsible for preventing excessive degradation of elastin. Deficiency would lead to too much neutrophil elastase = not enough elastin.
Condition is made worse by smokers.
Disease caused by mutations in fibrillin-1
Marfan syndrome
Symptoms are of what disease?
Very tall stature, kyphoscoliosis
Disproportionally long limbs, fingers and toes
Hyperflexible joints.
Dilation of the aorta
Heart valve problems
Disclocation of the lens of the eyes (ectopia lentis).
Marfan syndrome
The main receptors that anchor the cells to the extracellular matrix are
Integrins
These interactions are essential for the correct formation of basement membranes.
Integrin-laminin
Basement membrane proteins (characteristic cross-shape).
Laminins
Disease caused by mutations in certain laminins and integrins.
- Laminin and integrin deficiency
- Mainly affects the basement membrane below the epidermis and mucosal membranes.
- Main symptom is fragile skin that shows extreme blistering.
Epidermis separates from dermis
Junctional epidermolysis bullosa
