Flashcards in Role of Collagen in the Extracellular Matrix Deck (37)
Is collagen a glycoprotein?
Yes, it has sugars and are fully extracellular (not an integral membrane protein)
In the middle of a collagen triple-helix, what exists?
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)
Where is type I collagen typically found?
(main form) a fibrillar form typically found in bone, skin, tendons, cornea, and many other places (type V similar)
Where is type II collagen typically found?
a fibrillar form typically found in cartilage and the vitreous of the eye (type IX similar)
Where is type III collagen typically found?
a fibrillar form typically found in skin, blood vessels (often associated with type I)
Where is type IV collagen typically found?
a network form typically found in basal lamina sheets
Where is type VIII collagen typically found?
a network form typically form in endothelial lining and the cornea
T or F. All collagen are made of three helixes of polypeptides
What sequence do collagen fibers need to form triple helices?
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
Is there both intra-strand and inter-strand cross-linking of collagen?
Does type I collagen have the same three chains?
No, there are 2 alpha 1 chains and a single alpha 2 chain
T or F. Collagen self-assembles into small fibrils
T. Occurs after the collagen has been post-translationally modified and is completely mature
End to end aggregations of collagen fibrils form what?
collagen fibers. A single triple helix is called a collagen molecule, consisting of three polypeptide chains
What is a common cause of osteogenesis imperfecta?
a substitution of glycine for cysteine in collagen that makes the collagen weaker and deformed. Leads to multiple fractures in the patient
What causes the triple helix nature of a collagen helix?
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
How is proline converted to hydroxyproline?
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)
How is lysine converted to hydroxylysine in collagen?
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)
How can bone turnover be measured?
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
Where does collagen synthesis occur?
RER and golgi
What do the OH groups on collagen do?
They help assemble the three strands together by adding H+ bonds as the structure is forming which prevents melting (and subsequent degradation)
What must happen to collagen before it is mature?
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)
What are the steps of collagen biosynthesis?
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.)
Once assembled into fibers, what happens to newly formed collagen?
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
What is Ehlers- Danlos VI caused by?
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)
What is Ehlers- Danlos VII caused by?
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
What chemicals can inhibit lysyl oxidase?
lathrogens (causes disruption of cross-linking)
What is th Ehlers- Danlose IX caused by?
deficiency in lysyl oxidase so cross-linking cannot occur or is deficient
Substituting another AA for glycine in a collagen triple helix can result in what?
a destabilized triple helix
What disease results from failure to hydroxylate proline and lysine during collagen fiber formation?
scurvy (caused by vitamin C deficiency)
T or F. Collagen degradation is highly regulated
What is responsible for collagen degradation?
matrix metalloproteinases (MMPs). Involved in tissue development, wound healing, and inflammation. TIMPS regulate/inhibit the activity of MMPs.
MMPs are involved in cancer metastasis
MMP activity requires what?
activation of procollagenase
Does collagen type IV retain its globular end?
YES! so its not good for forming long ropes (Fibers) so they form tetramers
Collagen STABILITY is gained from what?
proline and lysine hydroxylation
Collagen STRENGTH is gained from what?
What does type IX collagen do?
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