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Biochem Exam 3 > L3.Extracellular Matrix > Flashcards

L3.Extracellular Matrix Flashcards

1
Q

What is the most abundant proteins of ECM? What family is this protein in?

A

Collagens. Part of the extracellular glycoprotein family.

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2
Q

What is the characteristic structure of Collagen? What are the three characteristic aas of collagen?

A

Triple Helix.

Glycine, Prolines, and Hydroxyprolines (hydroxylysines also present but not as common).

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3
Q

Does Hydroxyproline exist as a free aa? How is it formed?

A

No, hydroxyproline does not exist as a free aa. It is hydroxylated after proline is incorporated into a polypeptide chain. Note same for hydroxylysine!

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4
Q

Each polypeptide strand forms a unique polyproline type II helix. Can this structure be classified as an alpha-helix?

A

NO!

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5
Q

Where are Gly, Pro, Hyp, and peptide bonds located within the triple helix?

A

Gly = interior b/c small hydrophobic aa
Pro & Hyp = exterior b/c large ring structures sterically couldn’t fit anywhere else
Peptide Bonds = Interior b/c makes resistant to proteolytic degradation. Special enzymes required for collagen breakdown.

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6
Q

Describe

  1. Fibril-forming collagens
  2. Fibril-associated collagens
  3. Network-forming collagens
A
  1. Uninterrupted triple helical domain. Rather rigid
  2. Several non-triple helical domains provide some flexibility
  3. Many small non-triple helical domains. Quite flexible.
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7
Q

What type of Collagen are Type I, II, & III? Where is each found?

A

All Fibril-forming collagens
Type I: Major component of Bone. Also, tendons, skin, dentin, & perio ligament
Type II: Major component of Cartilage
Type III: Skin & Perio ligament

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8
Q

What type of collagen is Type IV? Where is type IV collagen found?

A

Network-forming collagen

Type IV: Basement Membranes

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9
Q

What are the four components of Pre-procollagen?

What role does the signal peptide play?

A
  1. Signal Peptide: Targets protein to ER/Secretory Pathway & is removed by Signal Peptidase as Procollagen moves into the ER
    2 & 3: N & C-terminal propeptides
  2. Triple helix domain ~1,000 aa
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10
Q

What is the first thing that happens to the pro-alpha chain after it enters the ER? What enzymes catalyze this event?

A

Hydroxylation of ~50% of Prolines and a few Lycines by Prolyl and Lysyl Hydroxylase respectively.

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11
Q

How will an Ascorbate (Vit C) deficiency effect the hydroxylation of Pro or Lys by prolyl or lysyl hydroxylase? Why?
-What will be the affect on cartilage?

A

Prolyl (Lysyl) hydroxylase uses Iron (Fe+2) as a cofactor to add 1 oxygen to Pro (Lys) and 1 oxygen to alpha-KG. During this process Fe+2 is oxidized to Fe+3. ASCORBATE (Vit C) is a REDUCING AGENT and is required to return FE+3 to its reduced Fe+2 state.
-Causes instability in collagens b/c no hydroxyprolines to form stabilizing H-bonding. Will probably be degraded at body temperature.

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12
Q

How do collagen pro-alpha chains begin Self-assembling into Procollagen?

A
  1. Disulfide bonds form between Cysteins on the C-terminus propeptides. Results in correct alignment of 3 subunits.
  2. Triple helix winds up from C-end to N-end. Resulting in formation of PROCOLLAGEN TRIPLE HELIX, which is shipped to the Golgi (where it is glycosylated) and then out of the cell.
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13
Q

The N- and C-terminal Propeptides are not removed until after the procollagen has been exported out of the cell. Why is this?

A

The N- & C-propeptides maintain procollagen in a soluble state. After the terminal propeptides are removed, the remaining collagen molecules spontaneously form into Collagen Fibrils. If this were to happen in the cell it would be very bad.

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14
Q

Once outside of the cell what enzymes facilitate the removal of the terminal propeptides? What structures are left at the poles of the collagen molecules (tropocollagen)? Purpose? How are collagen fibrils formed?

A

Endopeptidases remove the terminal propeptides.
Telopeptides are the new structures at the terminal end of the collagen molecules and form stabilizing covalent crosslinks with adjacent telopeptides.
-Collagen molecules then spontaneously polymerize into collagen fibrils.

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15
Q

What role does Lysyl Oxidase (Not to be confused with Lysyl Hydroxylase) play in forming covalent crosslinks between telopeptidases in collagen FIBRILS?
What effect do these crosslinks have on collagens stability?

A

Lysyl oxidase is a Cu2+ dependent enzyme that adds O2 to Lysine and Hydroxylysines to form two aldehyde derivatives. These aldehyde derivatives, located on adjacent collagen molecules, undergo a spontaneous aldol condensation reaction to form covalent aldol cross-links.
-These cross links make collagen incredibly stable. To isolate collagen you have to let it sit in acid for weeks to solubilize it

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16
Q

How are collagen fibers formed from fibrils?

A

Spontaneously

17
Q

Collagen Fibrils are always heterotypic. What does this mean in terms of tissue properties?

A

Collagen fibrils always contain more than one type of collagen. Thus, many tissue properties depend upon the ratios of the composition of collagen fibers within the fibrils.

18
Q

What are the 3 collagen fiber types in cartilage collagen fiber?

A
  1. Type II is main fiber. Linear fiber, forms core, provides rigidity.
  2. Type XI collagen has a kink with a domain that lies at the fibril surface
  3. Type IX is a fibril-associated collagen that lies on the fibril surface, which allows the fibril to interact with other matrix components.
19
Q

Type IV collagen is a network-forming collagen and is totally different than others we’ve seen. Why?

A
  1. Many imperfections
  2. Does not form fibrils
  3. Instead, forms flat, sheet like lattice or NETWORK with lateral and C-terminal interactions.
20
Q

Fibrotic disease?

A

Formation of excess fibrous connective tissue. Prevents funtional parts of tissue from performing fuction. Closely associated with TGF-beta (Transforming Growth Factor-beta).

21
Q

Osteogenesis Imperfecta?

A

Brittle Bone Disease - Type I collagen Mutation
Caused by mutations that replace Gly in the Triple helix interior with any other aa.
Mutations that replace Cys in the C-propetide with another amino acid. This causes disease b/c Cys form the initial disulfide bonds that results in procollagen triple helix formation.

22
Q

Ehlers-Danlos Syndrome (EDS)?

A

Mutations in Type I and III (III causes vascular type) collagen. Mutation in N-propeptide recognition site and mutations in lysyl oxide. But many many causes.
Joint hypermobility, skin elasticity and fragility, aortic aneurisms.

23
Q

What Collagen plays a role in regulating angiogenesis in tumor development?

A

Collagen Type XVIII = ENDOSTATIN

-Starves cancer tumors by cutting off blood supply.

24
Q

What is the structure of Proteoglycans?

A 
Proteoglycans are a class of glycoproteins with very high amounts of glycosylation. Highly variable
-Protein core (variable), with  numerous Covalently attached glycosaminoglycans (GAGs) (Also Variable).
25
Q

What are glycosaminoglycan (GAGs)?

A

Glycosaminoglycans are Unbranched PolySaccharides consisting of Repeating Disaccharides.
-Most are attached to proteoglycans

26
Q

What very important traitS make Hyaluronate unique from most other GAGs? How do these traits help with its function?

A

Hyaluronate does not have a NEGATIVE CHARGE due to attached SULFATE and Carboxyl groups. Also, Hyaluronate is NOT attached to a central protein. VERY LARGE.
-Hyaluronic acid is important in resisting compressive forces. Provides lubricant in joint. Binds to H2O, expands enormously.

27
Q

What is the function of Aggrecan? Where is it found? Functional structure?

A

Major Cartilage PG.
Forms large aggregates (~100 aggrecan monomers bound to HA)
Function: Ability of cartilage to resist compression is due to aggrecan.

28
Q

What is the function of Syndecan proteoglycan? What specific role does the GAG Heparan Sulfate (HS) on Syndecan play?

A

Transmembrane protein.
Acts as a low affinity co-receptor for Growth factors and ECM proteins.
ECM HS-PG complexes regulate FGF (fibroblast growth factor) availability by binding. FGF is released by PG degradation during tissue growth and wound repair. Now released to activate cell cycles, FGF must bind to its target receptor, however, FGF poorly recognizes its target so it must bind to HS-Syndecan FIRST (Why Syndecan is a CO-RECEPTOR). HS-Syndecan then transfers the FGF to its target receptor.

29
Q

What are the 3 components that make up elastic fibers? How do they form (3 basic steps)?

A
  1. Elastin
    2 & 3. Fibrillin 1 & 2
    Formation occurs via…
  2. Fibrillins form beads on a string structures that laterally associate to assemble into MICROFIBRILS.
  3. These microfibrils serve as a matrix for elastin deposition; forms tropoelastin. Occurs in a manner specific for mechanical demands of the tissue.
  4. Once transported out of cell, soluble tropoelastins form covalent crosslinks with help from Lysyl Oxidase enzyme(seen previously) into insoluble elastic fibers.
30
Q

Marfan syndrome and many lung diseases, such as chronic bronchitis, are associated with disruption in what ECM component?

A

ELASTIC FIBERS
Marfan Synd: Mutation in Fibrillin 1 gene
Supravalvular aortic stenosis: Mutation in Elastin gene

Biochem Exam 3 (10 decks)

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