CT 3 Flashcards
signals from the outside of the cell to stimulate gene transcription of Collagen
tgf beta il 1b
tnf alpha
signals from the outside of the cell to inhibit gene transcription of Collagen
TGF beta binds to
ser thre kinase activity
after ser thre kinase activity is triggered by TGF beta
SMAD 2 and 3 phosphorylate
phosphorylated SMAD 2 and 3
agg with SMAD 4 to form heterometric complex
heterometric complex
go to nucleus and act transcription of collagen
SMAD 7,8 inh
phos of SMAD 2 and 3
heterometric complex made from SMAD 2 and 3
binds CIS-elements in the 5′-flanking region for the regulation of transcription of the COL1A2 gene
collagen gene
repressors and enhancers
COL1 a1 controlled by
TGF beta act. protein
ColagenMolecule is to be secreted; it’s synthesized on —- —– ribosomes as larger precursor
Collagen Molecule is to be secreted; it’s synthesized on membrane-bound ribosomes as larger precursor
pre pro alpha chain (collagen)
hydrophobic and can be thread thru lumen of ER
pre pro alpha chain (collagen)
cotransltionally cleaved
signal peptidase
cleave N and C terminal
cleaveage of N and C terminal
leaves a telopeptide
contains intrachain disulfides
pN; N-terminal propeptide
contains interchain disulfides
pC; C-terminal propeptide
Collagens are modified
Collagens are modified after the amino acids are incorporated into the growing polypeptide chain
prolyl residues and lysyl residues
are hydroxylated
Glycosylation of—– residues
Glycosylation of hydroxylysyl residues
Prolyl hydroxylase has — ion at its active site
Prolyl hydroxylase has Fe++ ion at its active site
Prolyl hydroxylase
Prolyl hydroxylase is a dioxygenase
requires ascorbate
Prolyl hydroxylase
prolyl residue is added with —– —
and —to be hydrozylated
alpha ketogluterate and O2
Prolyl hydroxylase
act O2
Proline is hydroxylated at —-
by the action of prolyl hydroxylase
Proline is hydroxylated at C-4
by the action of prolyl hydroxylase
TF Free proline is a substrate
Free proline is NOT a substrate
Hydroxylation at C-4 only if Pro is on the —– side of a Gly residue in the (Gly-XY)n sequence in collagen
Hydroxylation at C-4 only if Pro is on the amino side of a Gly residue in the (Gly-XY)n sequence in collagen
Different enzyme; hydroxylation at —- if Pro is on the carboxyl side of a Gly in the (Gly-X-Y)n sequence in collagen
Different enzyme; hydroxylation at C-3 if Pro is on the carboxyl side of a Gly in the (Gly-X-Y)n sequence in collagen
3-prolyl hydroxylase
Dietary deficiency of vitamin C
Scurvy
Poor wound healing
Poor calcification of developing teeth
Vit C
Fragile blood vessels
Suppressed bone growth
Scurvy
gingival bleeding and
Skin lesions
deficiency of vitamin C
Hydroxylation of lysine only if it’s on the amino side of a glycine residue
Specificity of lysyl hydroxylase
O2 and ascorbate
needed for lysyl hydroxylase to work
α ketoglutarate; succinate
reactant and substrtae for lysyl hydroxylase and prolyl hydroxylase
Ehlers-Danlos Syndrome,
Deficiency of lysyl hydroxylase
❂ Hyperextensibility of skin and joints
Ehlers-Danlos Syndrome,
tf Ehlers-Danlos Syndrome, has inc crossliking of collagen
F
lowered
Poor wound healing
and Musculoskeletal deformities
Ehler danslos
Hyp
CANNOT be incorporated into a growing polypeptide chain so addition of [14C] Hyp will not result in formation of [14C] collagen
Proline and hydroxyproline are both radioactive but
Hyp CANNOT be incorporated into a growing polypeptide chain
Unique to collagens;
Unique to collagens; glycosylated hydroxylysyl residues
2 types of O linked glycosylations
serine and 5 hydroxylysine
asparagine
N glycosyl Linkage
glycosylations of
glucose and galactose
After post-translational modification, the 3 polypeptides associate to form the procollagen molecule.
After post-translational modification, the 3 polypeptides associate to form the procollagen (Type I procollagen) molecule.
where is procollagen made
in the ER lumen
Extension peptides
help guide the formation of the triple helix.
Each polypeptide is —- through a large portion of the molecule and stabilized partly by —— of the pyrrolidone rings of proline.
Each polypeptide is helical through a large portion of the molecule and stabilized partly by steric repulsion of the pyrrolidone rings of proline.
3 polypeptides (Pro α Chains) wind around each other to form a —- —–, with —— bonds between individual chains
3 polypeptides (Pro α Chains) wind around each other to form a —- —–, with —— bonds between individual chains
procollagen
Residues in each chain are —— staggered such that a gly, an X and a Y from ——chains are on the same level along the helix axis.
Residues in each chain are vertically staggered such that a gly, an X and a Y from different chains are on the same level along the helix axis.
procollagen
stiff cable
H-bonds form between —- and —- in procollagen
H-bonds form between the N-H of Gly and O in procollagen
procollagen C terminal
disulfide linkage
cooperative interactions
determines stability of collagen molecules
-NH of Gly and the C=O of second residue in triplet of neighboring chain
have a h bond
Gly as every third amino acid
Hyp content
Total imino acid content
determine stability of collagen molecule
inc temp
collagen loses its rodlike shape, the viscosity of the solution drops
helical structure destroyed
after TM
collagen is a random coil
Tm is the temperature at
temperature at which 1/2 of the helical structure is lost
abruptness of the transition indicates that the stability of collagen molecules depends upon—- cooperative interactions
abruptness of the transition indicates that the stability of collagen molecules depends upon weak cooperative interactions
abnormal collagen
smaller Tm
Hyp cntent
inc the TM and stabilizes the collagen triple helix
pro and hyp inc with
warm blooded animals
Tm also increases
H bonding in collagen occur
between peptide -NH of Gly and the C=O of second residue in triplet of neighboring chain
OH groups of Hyp also participate in Hbonding
Mutation of a single gly
can be lethal
close packing and stabilization of triple helix
Glycine
OI
Mutation of a single T for a G
glycine to cysteine mutation
OI
Skeletal deformities, brittle bones
OI
Triple helix is disrupted
OI
Rupture arteries
Rupture uterus
Ehlers-Danlos Syndrome, Type IV
Thin, translucent skin ,Bruise easily
Ehlers-Danlos Syndrome, Type IV
Perforate intestines
Ehlers-Danlos Syndrome, Type IV
Defects in type III collagen
Ehlers-Danlos Syndrome, Type IV
Gly , Skip exon
Ehlers-Danlos Syndrome, Type IV
