MBS 9 Protein Folding
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What are the two precursors of insulin?
preproinsulin (in cell) --> proinsulin (oxidized in ER) --> insulin (secreted & oxidized)
Collagen types I & III share:
- 1) collagen triple helix
- 2) modified amino acids (hydroxyproline and hydroxylysine)
Collagen type I
- • found in Bone (bONE), Skin, Tendon
- • composed of 2 alpha1 chains and 2alpha 2 chains
- • they have similar, not identical, AA sequences & are encoded by SEPARATE genes
Type I collagen is found in which tissues?
Bone, skin, tendons, heart valve
What parts of the cell are reducing? What parts are oxidizing and what affect does an oxidized environment have on a certain amino acid residue?
- • cytoplasm of cells = reducing
- • outside of cells, plasma, & ER lumen = oxidizing
- -sulfides on cysteine tend to form disulfide bonds with each other in an oxidizing environment
What are the steps of collagen biosynthesis? (9)
- • Shit Head Gary Doesn't Talk Smack, He Asks for X •
- 1) Synthesis of polypeptide chain
- 2) Hydroxylation of proline and lysine
- 3) glycosylation
- 4) disulfide bond formation at C-terminus
- 5) triple-helix formation
- 6) secretion
- 7) hydrolysis of propeptides
- • result = tropocollagen molecules
- 8) Assembly of fibril
- • result = collagen fibril
- 9) Fiber assembly and formation of cross (X) links
- • result = mature collagen fiber!
What steps of collagen synthesis are completed inside the cell and when is the protein secreted?
- • steps 1-5, up to triple helix formation occur inside the cell
- • after the triple helix is formed, a procollagen molecule is secreted from the cell to undergo C and N-terminus hydrolysis (severing), spontaneous assembly into a fibril, then cross-linking and further & final fiber formation
What's the difference between lysyl hydroxylase and lysysl oxidase?
- • lysyl hydroxylase (step #2): catalyzes hydroxylation of lysine to hydroxylysine
- • lysyl oxidases (step #9): oxidizes NH3+ group at the end of the lysyl side-chain resulting in formation of modified amino acid residue --> allysine
- • allysine condenses with the side-chain of an unmodified lysine forming a covalent cross-links in mature collagen
What are the two modified amino acids present in collagen?
hydroxyPROLINE and hydroxyLYSINE
hydroxyproline content determines:
stability of the collagen helix
What type of enzyme (and co-factor) hydroxylate the two amino acids that get hydroxylated during collagen formation?
prolyl and lysyl hydroxylase and the cofactor ascorbic acid (form of Vitamin C)
What causes collagen to form a triple helix rather than a standard alpha helix or beta sheet?
the steric repulsion between the prolines and hydroxyprolines
Where is glycine found in collagen?
it's typically found at every third residue
collagen triple helix
- collagen adopts a secondary structure formed by H-bonding among the three chains, which involves the NH groups of glycine on one chain and the COOH group on an adjacent chain
- • a glycine at every 3rd residue allows close packing of each helical segment (it's small size allows close approach of the chains in the triple helix)
- • A MUTATION WOULD DISRUPT ASSEMBLY!
What form of collagen is made after hydrolysis of procollagen?
Tropocollagen; these molecules spontaneously assemble to form a collagen fibril
the gap between tropocollagen molecules is important for:
bONE formation (collagen forms the matrix on which calcium phosphate is deposited during osteogenesis)
What enzyme helps catalyze the formation of cross links in mature collagen fibers?
lysyl oxidase oxidizes lysine to allysine; this forms a cross-link with unmodified lysines
What causes scurvy?
- A lack of ascorbic acid (Vitamin C) which leads to a decrease in the hydroxylation of lysines and prolines in collagen
- • makes unstable collagen
samage and fragility of many tissues and organs such as the gums, as well as skin lesions and blood vessel fragility
Which condition usually results from a mutation in type I collagen?
• a severe forms of the mutation replaces collagen's glycine with a cysteine --> interfering with the collagen triple helix.
What are the symptoms of Osteogenesis Imperfecta?
- clinical correlate: gonadal mosaicism, COLLAGEN
- Symptoms: bone deformities, fragile blood vessels, and brittle bones & teeth
What kind of bond holds the two peptide chains of collagen to one another?
disulfide bonds and non-covalent interactions
What are two causes of Ehlers-Danlos Syndrome?
- 1) Improper processing of collagen caused by lack of enzyme (eg. lysyl oxidase deficiency)
- 2) genetic defects in the collagen genes
What are the symptoms of Ehlers-Danlos Syndrome?
hyperelastic joints and skin hyper-extendibility
Keratin is a protein rich in which amino acid?
What is the basic structural unit of collagen?
the collagen triple helix
True or False: different types of collagen arise from alternative splicing?
FALSE: different types of collagen are encoded by separate genes
Type II collagen is typically found in which tissues?
Type IV collagen is typically found in which tissues?
Which enzyme catalyzes the hydroxylation of proline into hydroxyproline?
Which enzyme catalyzes the hydroxylation of lysine into hydroxylysine?
Vitamin C is a cofactor for the hydroxylation of which amino acid present in collagen?
What kind of bond predominates between the three chains of a collagen triple helix?
Hydrogen bonding between the NH groups of glycine on one chain and the carboxyl groups on another chain
True or False: collagen processing and assembly occur outside the cell (i.e. in the extracellular space)
What is the difference between procollagen and tropocollagen?
Tropocollagen molecules lack the N & C-terminus' of procollagen and can SPONTANEOUSLY assemble into collagen fibrils
In which tissues are elastin fibers typically found?
In elastic tissues such as the lungs
What is the most common cross-linkage between elastin molecules?
Desmosine linkage, which involves four lysines
In which tissues is keratin typically found?
Hair and nails
Examples of transmissible spongiform encephalopathies:
- • Mad Cow disease
- • Scrapie (sheep)
- • Creutzfeldt-Jakob disease
- • Kuru
What causes Transmissible spongiform encephalopathies?
- 1) Inherit a missense mutation (eg. Creutzfeldt-Jacob disease)
- 2) Come into contact with "bad" form of the protein
- • prion protein can exist in either a soluble or aggregated form; aggregated forms are disease causing
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