Chapter 4: Fibrous Proteins

collagen

most abundant protein in the body

ECM

collagen and elastin are proteins of the __

long,rigid structure with 3 polypeptides (α chains) wound around one another in rope-like triple helix

typical collagen structure?

>25

superfamily of proteins includes __ collagen types?

two chains called α1 and one chain called α2 (α12α2)

collagen type 1 contains what chains?

three α1 chains (α13)

collagen type 2 contains what chains?

fibril-forming

collagen type 1,2,3 are what group collagen?

network-forming

collagen type 4 & 8 are what group collagen?

fibril-associated

collagen type 9 & 12 are what group collagen?

Fibril-associated collagens with interrupted triple helices

What is FACIT?

banding pattern

the fibril forming collagens (1,2,3) have characteristic...?

high tensile strength elements:
skin, bone, tendon, blood vessels, cornea

collagen type 1: tissues?

cartilage, intervertebral disk, vitreous body

collagen type 2: tissues?

blood vessels, skin, muscle

collagen type 3: tissues?

basement membrane

collagen type 4: tissues?

corneal and vascular endothelium

collagen type 8: tissues?

cartilage

collagen type 9: tissues?

tendon, ligaments, some other tissues

collagen type 12: tissues?

glycine and proline

collagen is rich in which AA?

formation of the helical conformation of each α chain - ring structure causes "kinks" in the peptide chain

proline facilitates...?

helical conformation of the α chain cannot be an α helix

what does the the presence of proline in collagen dictate?

Glycine

what is the smallest AA?

3rd

glycine is found in every which position in polypeptide chain?

−Gly-X-Y-

X is frequently proline, and Y is hydroxyproline (or hydroxylysine)

glycine residues are part of which repeating sequence?

hydroxyproline and hydroxyproline

collagen contains which nonstandard AA?

hydroxylation of some of the proline and lysine residues after their incorporation into polypeptide chains

hydroxyproline and hydroxyproline (in collagen) results from..?

posttranslational

therefore: hydroxylation is what type of modification?

interchain hydrogen bonds that stabilize the triple-helical structure

Generation of hydroxyproline maximizes formation of what?

hydroxyl group of the hydroxylysine residues

what can be enzymatically glycosylated in collagen?

to polypeptide chain prior to triple-helix formation

glucose and galactose are sequentially attached to... before ....?

fibroblasts, or osteoblasts and chondroblasts

polypeptide precursors of the collagen molecule are synthesized in...?

ECM

after enzymic modification and formation of triple helix, it gets secreted into..?

aggregate, become cross-linked to form collagen fibers

additional enzymic modification -> what happens to mature extracellular collagen fibrils?

prepro-α chains

newly synthesized polypeptide precursors of α chains are called =

binding of ribosomes to RER and directs passage of the prepro-α chain into the lumen of the RER

prepro-α chains contain signal sequence that facilitates..?

pro-α chain

the signal sequence is rapidly cleaved in the lumen to yield a precursor of collagen called..?

1. Pro-α chain formation
2. Hydroxylation
3. Glycosylation
4. Assembly and secretion
5. Extracellular cleavage of procollagen molecules
6. Collagen fibril formation
7. Cross-link formation

steps of collagen biosynthesis

triple helix; nonhelical N- and carboxyl (C)-

procollagen has a central region of ... flanked by the... terminal extensions called propeptide

disulfide bonds between c terminal extensions of pro α chain

procollagen formation begins with formation of ?

golgi; secretory vesicles (vesicles fuse with membrane, release into extracellular space)

procllagen moves through ... and fuses with?

N- and C- procollagen peptidases

triple-helical procollagen molecules are cleaved by...?

terminal propeptides, producing tropocollagen molecules

N- and C- procollagen peptidases remove and produce what?

lysyl oxidase

the fibrillar array of collagen molecules serves as a substrate for..?

two allysine

Cross-links can form between what residues?

reactive aldehydes (allysine and hydroxyallysine);

can spontaneously condense with lysine or hydroxylysine residues to form covalent cross-links and, thus, mature collagen fiber

lysyl oxidase oxidatively deaminates some of the lysine and hydroxylysine residues in collagen. what is the result?

by a toxin present in seeds from Lathyrus odoratus (sweet pea)

what is lysyl oxidase irreversibly inhibited by?

lathyrism that is characterized by skeletal and vascular problems

inhibition of lysyl oxidase by Lathyrus odoratus leads to...? characterized by?

several years

half life of collagen

on proteolytic action of collagenases (part of a large family of matrix metalloproteinases)

Breakdown of collagen fibers is dependent...?

at specific sites: generating three-quarter and one-quarter

in type 1 collagen the cleavage produces ___ length fragments

matrix proteinases

collagen fragments can be further degraded by

Ehlers-Danlos syndrome
Osteogenesis imperfecta

Collagenopathies examples

heteregenous

EDS is a ___ group of CT disorders

deficiency of collagen-processing enzymes (e.g. lysyl hydroxylase or N-procollagen peptidase)
or from mutations in the amino acid sequences of collagen types I, III, and V

what can EDS be caused by..?

defects in type V collage; by skin extensibility and fragility and joint hypermobility

classic form of EDS is caused and characterized by:

vascular form: defects in type III collagen (potentially lethal arterial rupture)

most serious form of EDS: due to defects in..?

autosomal- dominant inheritance

inheritance pattern of classic and vascular form of EDS?

Incorporation of just one mutant chain may result in degradation of the triple helix

what is dominant-negative effect?

karteikarte

Osteogenesis imperfecta

glycine (in -Gly-X-Y-) by amino acids with bulky side chains

Osteogenesis imperfecta: most common mutations cause replacement of...?

type 2

the lethal form of Osteogenesis imperfecta?

rubber

elastin has ___ -like properties

insoluble

is elastin soluble or insoluble?

tropoelastin

elastin is generated from precursor...

soluble; 700 (primarily small and nonpolar: glycine, alanine, and valine)

tropoelastin is a ... polypeptide composed of .... AA

proline, glycine

Elastin is rich in which 2 amino acids?

hydroxyproline and hydroxylysine

Elastin contains scant...

ECM

tropoelastin is secreted into

specific glycoprotein microfibrils, like fibrillin - function as a scaffold onto which tropoelastin is deposited

in ECM tropoelastin interacts with...? that functions as?

some lysyl side chains; forming allysine residues

what is oxidatively deaminated by lysyl oxidase of tropoelastin? what is formed?

3 of the allysyl side chains plus 1 unaltered lysyl side chain (from same or neighboring polypeptides)

-> producing elastin

what forms a desmosine cross link (elastin) ?

impaired structural integrity in the skeleton, the eye, and the cardiovascular system (rest karteikarte)

marfan syndrome is characterized by

Marfan syndrome, OI, or EDS

patients with which diseases may have blue sclerae?

proteolytic enzymes (peptidases, proteases, or proteinases)

trypsin

α1-antitrypsin (AAT) inhibits:

neutrophil elastase (a powerful elastase)

what important physiologic role does AAT have? inhibiting..?

extracellular space; degrades elastin of alveolar walls

elastase is released into ... and degrades ...

liver

most of AAT in plasma is synthesized and secreted by ...?

neutrophils activated as part of the immune response to airborne pathogens

Elastase is released from ... as a response to?

no

can lung tissue regenerate?

GAG to AAG, resulting in the substitution of lysine for glutamic acid at position 342 of the protein

mutated protein is termed the Z variant

most widespread and severe gene mutation responsible for α1-Antitrypsin deficiency?

358

Methionine ___ in AAT is required for the binding of the inhibitor to its target proteases

causes the oxidation and subsequent inactivation of the methionine

smoking renders AAT powerless to neutralize elastase how?

weekly augmentation therapy: intravenous administration of AAT

how can deficiency of elastase inhibitor be treated?