Role of Collagen in the Extracellular Matrix

Question 1

Is collagen a glycoprotein?

Answer 1

Yes, it has sugars and are fully extracellular (not an integral membrane protein)

Question 2

In the middle of a collagen triple-helix, what exists?

Answer 2

a hydrogen side chain (from glycine). Every third residue in normal collagen is glycine ya bish. Replacing glycine with another AA (which are gonna be bigger) causes the barrel to bulge and the collagen would be weaker and are more rapidly degraded (recognized as an unfolded protein)

Question 3

Where is type I collagen typically found?

Answer 3

(main form) a fibrillar form typically found in bone, skin, tendons, cornea, and many other places (type V similar)

Question 4

Where is type II collagen typically found?

Answer 4

a fibrillar form typically found in cartilage and the vitreous of the eye (type IX similar)

Question 5

Where is type III collagen typically found?

Answer 5

a fibrillar form typically found in skin, blood vessels (often associated with type I)

Question 6

Where is type IV collagen typically found?

Answer 6

a network form typically found in basal lamina sheets

Question 7

Where is type VIII collagen typically found?

Answer 7

a network form typically form in endothelial lining and the cornea

Question 8

T or F. All collagen are made of three helixes of polypeptides

Answer 8

T.

Question 9

What sequence do collagen fibers need to form triple helices?

Answer 9

Gly-X-Y. The X and Y positions are often (not always) filled with proline and hydroxyproline AAs. Cross-linking of polypeptides provides the strength to withstand stress

Question 10

Is there both intra-strand and inter-strand cross-linking of collagen?

Answer 10

Yes

Question 11

Does type I collagen have the same three chains?

Answer 11

No, there are 2 alpha 1 chains and a single alpha 2 chain

Question 12

T or F. Collagen self-assembles into small fibrils

Answer 12

T. Occurs after the collagen has been post-translationally modified and is completely mature

Question 13

End to end aggregations of collagen fibrils form what?

Answer 13

collagen fibers. A single triple helix is called a collagen molecule, consisting of three polypeptide chains

Question 14

What is a common cause of osteogenesis imperfecta?

Answer 14

a substitution of glycine for cysteine in collagen that makes the collagen weaker and deformed. Leads to multiple fractures in the patient

Question 15

What causes the triple helix nature of a collagen helix?

Answer 15

the presence of proline and hydroxyproline (at X and Y- remember that X and Y can be ANY AA but they are typically proline and hydroxyproline) cause the polypeptides to deform. These are responsible for the coiled nature and adding RIGIDITY to the coil

Question 16

How is proline converted to hydroxyproline?

Answer 16

it is acted upon by prolyl hydroxylate in a VITAMIN C dependent step (using akG, Fe2+, and O2 and giving off Co2 and succinate)

Lack of vitamin C causes scurvy (collagenous tissue get weak and sores bleed)

Question 17

How is lysine converted to hydroxylysine in collagen?

Answer 17

it is acted upon by lysyl hydroxylate in a VITAMIN C dependent step (the hydroxylysine is then O-glycoslyated, but NEEDS to be hydroxylated in order for that to happen. I.E. no hydroxylation= no glycosylation).

Lack of vitamin C causes scurvy (vitamin C high in fruits and veggies)

Question 18

How can bone turnover be measured?

Answer 18

measuring hydroxyproline in the urine (once its lost, it is NOT reused by other collagen because it is a post-translational modification).

NOTE: patients should avoid jello before this test because jello contains gelatin, which is denatured collagen

Question 19

Where does collagen synthesis occur?

Answer 19

RER and golgi

Question 20

What do the OH groups on collagen do?

Answer 20

They help assemble the three strands together by adding H+ bonds as the structure is forming which prevents melting (and subsequent degradation)

Question 21

What must happen to collagen before it is mature?

Answer 21

the pro peptidase sequences must be cleaved on the outside of cells and lysyl oxidase then acts to cross-link them (using O2 and releasing NH3)

Question 22

What are the steps of collagen biosynthesis?

Answer 22

1) In the RER, a nascent polypeptide is made by a ribosome with a pro-peptide of collagen and gly-XY repeats
2) vitamin C dependent hydroxylation of selected proline and lysines
3) glycosylation of selected hydroxylysines
4) self-assembly of the three pro-a chains (C terminal pro-collagen propeptide domains help align the three chains in the proper orientation for formation)
5) the assembled triple helix is secreted to the extracellular space and then joined to others to form a fibrils
6) cleavage of globular (not linear or helical) pro-peptide ends and then formation of fibers (globular heads would prevent the formation of FIBERs if left on the molecule and can cause dermatosparaxis, fragile skin, etc.)

Question 23

Once assembled into fibers, what happens to newly formed collagen?

Answer 23

the collagen fiber must be colavently linked after lysyl oxidase forms aldehydes (removing an amine group) of lysines and hydroxylysines. The aldehyde and a second lysine residue can spontaneously combine to form a schiff base, which is an intermolecular covalent cross-link of collagen fibers. This adds STRENGTH to withstand pulling forces

Question 24

What is Ehlers- Danlos VI caused by?

Answer 24

a defect in lysyl hydroxylate that hydroxylated some lysines to form hydroxylysines so that they can be glycosylated. Vitamin C is needed for this reaction (thus scurvy can also be a result of this step)

Question 25

What is Ehlers- Danlos VII caused by?

Answer 25

N-propeptidase deficiency causing deficiency of this enzyme to remove the pro-peptide region of the collagen fibrils once they are secreted outside of the cell before they become FIBERS (not cross-link related)

causes Dermatosporaxis in cattle

Question 26

What chemicals can inhibit lysyl oxidase?

Answer 26

lathrogens (causes disruption of cross-linking)

Question 27

What is th Ehlers- Danlose IX caused by?

Answer 27

deficiency in lysyl oxidase so cross-linking cannot occur or is deficient

Question 28

Substituting another AA for glycine in a collagen triple helix can result in what?

Answer 28

a destabilized triple helix

Question 29

What disease results from failure to hydroxylate proline and lysine during collagen fiber formation?

Answer 29

scurvy (caused by vitamin C deficiency)

Question 30

T or F. Collagen degradation is highly regulated

Answer 30

T.

Question 31

What is responsible for collagen degradation?

Answer 31

matrix metalloproteinases (MMPs). Involved in tissue development, wound healing, and inflammation. TIMPS regulate/inhibit the activity of MMPs.

MMPs are involved in cancer metastasis

Question 32

MMP activity requires what?

Answer 32

activation of procollagenase

Question 33

Does collagen type IV retain its globular end?

Answer 33

YES! so its not good for forming long ropes (Fibers) so they form tetramers

Question 34

Collagen STABILITY is gained from what?

Answer 34

proline and lysine hydroxylation

Question 35

Collagen STRENGTH is gained from what?

Answer 35

cross linking

Question 36

What does type IX collagen do?

Answer 36

it is a ‘fiber associated collagen’ located on the ends of type II collagen and are composed of collagen and proteoglycans in order to limit the size of type II fibers

oriented perpendicular to the main collagen to which they are attached

Question 37

What is type XI collagen?

Answer 37

a fiber associated collagen for type I collagen