CT 3 Flashcards by Sumit Puri

signals from the outside of the cell to stimulate gene transcription of Collagen

tgf beta il 1b

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tnf alpha

signals from the outside of the cell to inhibit gene transcription of Collagen

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TGF beta binds to

ser thre kinase activity

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after ser thre kinase activity is triggered by TGF beta

SMAD 2 and 3 phosphorylate

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phosphorylated SMAD 2 and 3

agg with SMAD 4 to form heterometric complex

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heterometric complex

go to nucleus and act transcription of collagen

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SMAD 7,8 inh

phos of SMAD 2 and 3

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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

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collagen gene

repressors and enhancers

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COL1 a1 controlled by

TGF beta act. protein

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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

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pre pro alpha chain (collagen)

hydrophobic and can be thread thru lumen of ER

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pre pro alpha chain (collagen)

cotransltionally cleaved

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signal peptidase

cleave N and C terminal

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cleaveage of N and C terminal

leaves a telopeptide

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contains intrachain disulfides

pN; N-terminal propeptide

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contains interchain disulfides

pC; C-terminal propeptide

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Collagens are modified

Collagens are modified after the amino acids are incorporated into the growing polypeptide chain

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prolyl residues and lysyl residues

are hydroxylated

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Glycosylation of—– residues

Glycosylation of hydroxylysyl residues

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Prolyl hydroxylase has — ion at its active site

Prolyl hydroxylase has Fe++ ion at its active site

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Prolyl hydroxylase

Prolyl hydroxylase is a dioxygenase

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requires ascorbate

Prolyl hydroxylase

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prolyl residue is added with —– —

and —to be hydrozylated

alpha ketogluterate and O2

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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

Mutation of a single T for a G

glycine to cysteine mutation

Skeletal deformities, brittle bones

Triple helix is disrupted

Rupture arteries Rupture uterus