2.6.1. Part 1 of 2 Collagen and Proteoglycan (Collagen Only) Flashcards
Difference between the purposes of collagen and elastin
Collagen provides tensile strength
Elastin provides elasticity
What does laminin do?
provides meshwork and anchor points
What is the most abundant protein in the body?
Collagen
Where are different types of collagen found? Provide the pneumonic
Be So Totally Cool, Read Books
Bone, Skin, Tendon, Cartilage (incl hyaline), Reticulin, Blood vessels
Discuss what falls into the category of Type I collagen and how much of it we see in the body
accounts for 90% of the total body collagen and occurs in the skin, bone, tendons, cornea, soft tissues, and scars.
Which collagen type has the least amount of ccarbohydrate? Most amount?
Type I has the least, Type IV has the most
Osteogenesis Imperfecta is caused by genetic defects in what collagen type?
Type 1
Where does Type II cartilage occur? What chain type is associated with it?
occurs in cartilage (made by chondrocytes) and vitreous humor.
Chain type c3
Type II is the major type found in cartilage. But where do we also find it?
Skin and tendon
Where do we find Type III collagen and what is it chain type?
Chain type d3
occurs mainly in blood vessel walls, other hollow organs, and fetal skin. Found in scars and all adult soft tissues, but not in bone or tendons
Two collagen types have something structurally unique about them. Which ones and what is the difference?
Type III and IV contain disulfide bridges between chains whereas type I and II do not.
What disease is associated with defects in type III collagen?
Ehlers-Danlos Type 4 disease
Defects associated with Ehlers-Danlos?
Aortic rupture GI tract Pregnancy problems Skin fragility Poor wound healing Surgical problems
Describe Type IV collagen and the chain type
e3 chain type
the collagen of basement membranes (mesh-forming; creates hexagonal lattices).
What is the chain type for Type I collagen?
a2b
Why can Type IV cartilage allow for interruptions in the triple helix?
Due to high carbohydrate content
Defects in Type IV can cause what?
Alport syndrome
What is Alport disease characterized by?
Alport syndrome is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities.
What causes Goodpasture’s syndrome?
Autoantibodies target Type IV collagen
What characterizes Goodpasture’s syndrome?
group of acute illnesses involving the kidneys and lungs
What types of scars have collagen deposition and in what arrangement is it deposited?
collagen synthesis is increased in hypertrophic scar formation (w/parallel arrangement), and drastically increased in keloid scar formation (w/disorganized arrangement)
Primary shape of collagen?
Rod
Secondary shape of collagen?
Regular - 3 polypeptide chains with at least one stretch wound together to form a triple-helix
How soluble is collagen in water?
It has low solubility in water
How many exons are there in fibrillar collagen genes?
42
All Collagen has a central region that encodes what? What repeating unit is associated with this stretch?
All collagens have a central region that encodes a 1014 amino acid stretch with the repeating unit (Gly-X-Y) 338 times
What two amino acids are present in the Y position of the repeating units in Collagen?
Recall: All collagens have a central region that encodes a 1014 amino acid stretch with the repeating unit (Gly-X-Y) 338 times
Hydroxyproline and hydroxylysine
Recall: All collagens have a central region that encodes a 1014 amino acid stretch with the repeating unit (Gly-X-Y) 338 times
What is usually in the x position?
Proline
What is important about the y residues?
Recall: All collagens have a central region that encodes a 1014 amino acid stretch with the repeating unit (Gly-X-Y)338
Hydroxylation of the Y residues results in a polar surface that stabilizes the overall structure by forming H-bonds with water
What residues are positioned in the central axis between the helices?
Glycine
When is procollagen formed?
Procollagen is formed from preprocollagen after removal of the signal peptides in the ER
What are the domains of preprocollagen?
Globular (N and C terminal)
Triple helical
Non-triple helical
What exactly causes, in procollagen, Ehlers-Danlos Type VII?
Failure to cleave the N-terminal domain due to a defective N-terminal peptidase results in Ehlers-Danlos type VII
A defect in which terminal of the collagen is worst? Why?
C terminal defect due to the direction of the helix coiling.
The presence of what amino acid is a good indicator of collagen synthesis?
Glycine
What parts of collagen synthesis occur inside the fibroblasts?
Synthesis
Hydroxylation
Glycosylation
Exocytosis
What occurs during the synthesis step of collagen formation? Where in the fibroblast does it occur?
Synthesis (RER)
Translation of alpha chains (pre-procollagen), usually as Gly-X-Y, where X = proline and Y = lysine
What occurs during the hydroxylation step of collagen formation? Where in the fibroblast does it occur?
Hydroxylation (RER)
Specific Pro and Lys residues are hydroxylated
What cofactors are required for hydroxylation?
This requires Vitamin C and Fe2+ as cofactors
What happens with a deficiency of Vitamin C?
Scurvy
What characterizes scurvy?
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.
What happens during the glycosylation step of collagen synthesis? Where in the fibroblast does it occur?
Glycosylation (RER)
Pro-alpha-chain hydroxylysine residues are glycosylated
Procollagen is formed via hydrogen and disulfide bonds (this is where the triple helix takes shape - after this shape is made, no more modification can occur on the individual fibers!)
What causes Osteogenesis Imperfecta in the synthesis of collagen process?
Glycosylation process
Problems forming this triple helix leads to Osteogenesis Imperfecta
Describe the exocytosis step out of the fibroblast. What is important about the status of the collagen?
Procollagen is exocytosed into the ECM
Note that the molecule is still in its “pro” form - if it was cleaved before, it couldn’t be transported out :(
What steps of colagen synthesis occur outside of the fibroblast?
Proteolytic processing
Cross-linking
Describe proteolytic processing
Disulfide-rich terminal regions are cleaved within procollagen, transforming it into an insoluble tropocollagen
What occurs during the cross linking phase? What happens when there is a problem in this process?
Many staggered tropocollagen molecules are reinforced by covalent lysine-hydroxylysine cross-linkages
Problems with cross-linking results in Ehlers-Danlos
What other ingredients besides the developing collagen is important for the cross linking step?
This is accomplished by the Cu2+ containing lysyl oxidase (NOT HYDROXYLASE) , thus creating collagen fibrils
What happens with a deficiency in lysyl hydroxylase?
ED type VI
ED Type VI phenotype?
skin bruising, hyperextensible skin, joint hypermobility
What happens with a Cu2+ deficiency?
Cu2+ deficiency presents with connective tissue dysfunction, because collagen synthesis isn’t properly executed
Types of ED and what causes them?
Hypermobility type (joint instability) = most common type
Classical type (joint and skin symptoms) = caused by a mutation in Type 5 collagen
Vascular type (vascular & organ rupture) = caused by deficient Type 3 collagen
What happens with a deficiency in ascorbic acid?
scurvy [decreased hydroxyproline synthesis]
Describe the general manifestations of osteogenesis imperfecta
multiple fractures w/minimal trauma, that may occur during the birthing process
hearing loss (b/c the ossicles are abnormally formed)
dental imperfections due to the lack of dentin
Describe Type I Osteogenesis Imperfecta. What clinical signs do we see and how can we test for it?
Type I: mild form; blue sclera, mild to moderate decrease in the bone mass, generally normal life span. Autosomal dominant, decrease in the amount of Type I collagen; fractures seen in infancy and childhood, decrease over time, but non-deforming
May incorrectly assume child abuse
the blue sclera results from the translucency of the CT over the choroidal veins
Discuss type II osteogenesis imperfecta. What causes it, how does it present, and how can we diagnosis it?
Type II: perinatal lethal form; dark sclera, severe bone fragility, absent calvarial mineralization, bony compression.
Caused by exon skipping mutations and deletions, and glycine substitutions due to point mutations.
AD inheritance as well, diagnosed in utero by ultrasound
Undermineralized bones, marked bowing of extremities, flattened vertebral bodies (can be seen on x-ray)
What is Menkes Disease? How does it present and what causes it?
A type of CT disease caused by impaired copper absorption and transport
Leads to DECREASED lysyl oxidase activity (requires Cu2+ as a cofactor)
Due to the inability to tie the loose ends of collagen molecules, brittle, “”kinky” hair is seen, along with growth retardation and hypotonia
