fibrous proteins and connective tissue diseases Flashcards
what is the most abundant protein in mammals?
collagen; 25-35% of total body protein
what percent of collagen in the body is type I?
90%
where is the highest concentration of collagen in the body?
connective tissues-
fibril-forming collagen
-skin, bone, tendon, blood vessels, cornea
Type I
network-forming collagen
-basement membrane
Type IV collagen
what are the steps of collagen biosynthesis?
1) genes for pro-alpha1 and pro-alpha2 chains are transcribed into mRNAs
2) mRNA is translated on the RER into prepro-a-polypeptide chains that are extruded into the lumen of the RER, where the signal sequence is removed
3) selected proline and lysine residues are hydroxylated
4) selected hydroxylysine residues are glycosylated with glucose and galactose
hydroxylation of proline and lysine residues occurs as ___________________________
the prepro-a-chain is being translated
what is required to keep hydroxylases active
Vitamin C (ascorbate)
what enzyme hydroxylates proline
prolyl hydroxylase
what enzyme hydroxylates lysine
lysyl hydroxylase
describe the composition of pro-a-chains
-the middle region is composed of similar tripeptide repeats
-glycine occupies every third position in the middle region
-the N & C terminal regions form globular domains
what are the component of the triple helix
-two pro-a1 and one pro-a2
-stabilized by extensive hydrogen bonding made possible by the hydroxyproline side chains
__________________forms between globular C terminal domains of pro-a chains and initiates the winding of three chains into a triple helix
disulfide bonds
do globular C or N terminal chains have disulfide bonds
only C
the triple helix plus the globular C-terminal and N-terminal domains are called ___________________, secreted from fibroblasts
procollagen
Outside of the cell, the N and C domains of procollagen are……..
removed by procollagen peptidases to produce mature collagen
mature (tropo-) collagen organizes spontaneously into ____________________
fibrils
collagen fibril structure is stabilized by _______________between the mature collagen molecules
covalent cross-links
describe the stabilization process of collagen fibrils
-lysyl oxidase deaminates lysine
-converts its delta carbon to an aldehyde (allysine)
-aldehyde reacts with epsilon amino group of a lysine on another collagen chain
-forms cross-link in the developing collagen fibril
________________cross-links form between multiple allysine, hydroxyallysine, and lysine side chains.
hydroxypyridinium and desmosine
osteogenesis imperfecta
-britte bone disease
-characterized by frequent bone breaks
-can occur in utero
-can be mild, severe, or perinatal lethal
-caused by mutations that cause decreased type I collagen production
-dominant or recessive
what are symptoms of osteogenesis imperfecta
-bones likely to break from mild to moderate trauma, mostly occurring before puberty
-no change or only slight changes to stature with aging
-loose joints and muscle weakness
-blue, purple, gray tint to sclera (whites of eyes)
-triangular face
-curved spine with potential for compression of vertebrae with aging
-mild or no bone deformity
-possible changes to the strength and color of teeth
-possible hearing loss
what are treatment options for osteogenesis imperfecta?
-biphosphonate drugs (inhibit osteoclast activity & allows more time for collagen type I to accumulate)
-analgesics for bone pain
describe the severe types of osteogenesis imperfecta
-types II-VII
-mutations substitute a residue with a larger side chain for a single glycine in the tripeptide repeat region of a pro-a-chain of procollagen
-alters ability to form triple helix & mechanical properties
-short stature, fragile bones, thin skin, abnormal teeth and week tendons, barrel chest, triangular face, breathing problems
-treatment is surgery, orthotics, analgesia
which type of collagen is neonatal lethal?
type II
Ehlers-Danlos syndrome
-joint hypermobility, skin hyperextensibility, soft skin and easy bruising
-mutations in type III, V, and I collagen, lysyl hydroxylase and procollagen N-terminal peptidase
epidermolysis bullosa
-fragile skin, blisters easily
- 4 types, depending on where the defect occurs in the epithelium
-correlates to mutations in different collagen
blisters occur in the lower part of the epidermis
epidermolysis bullosa simplex
blisters occur in the top portion of the basement membrane
junctional epidermolysis bullosa
blisters occur in the upper dermis
dystrophic epidermolysis bullosa
blisters happen in multiple layers of the skin, including the basement membrane
Kindler syndrome
Alport syndrome
-defect in type IV collagen, rare
-affects kidneys, eyes, hearing
-defects in basement membranes, particularly in glomeruli
-three inheritance patterns
X-linked Alport syndrome
-80% of cases
-without treatment, 90% of males develop kidney failure by 40 years old
-females develop kidney failure less frequently and more slowly
-defects in COL4A5
Autosomal recessive Alport syndrome
mutations in COL4A3 and COL4A4
Autosomal dominant Alport syndrome
mutations in COL4A3 and COL4A4
what are the symptoms of Alport syndrome
-blood in urine (hematuria) (most common & earliest sign)
-protein in urine (proteinuria)
-high blood pressure
-swelling in the legs, ankle, feet, and around eyes
how is Alport syndrome diagnosed
-urine test
-blood test
-Glomerular filtration rate (monitor kidney function)
-kidney biopsy
-hearing test
-vision test
-genetic test
what is used for treatment of Alport syndrome
-hypertension control
-diuretics
-limit dietary sodium
-kidney transplant
what causes scurvy
-incomplete hydroxylation of prolines and lysines due to Vitamin C deficiency
-decreases the number of H bonds necessary to stabilize the triple helix in all types of collagen
what are the symptoms of scurvy
-capillary fragility
-spongy gums
-poor wound healing
-fatal if untreated
elastic fibers stretch up to _______in length
150%
where are elastic fibers predominantly found
skin, walls, arteries, and lungs
energy stored in elastic fibers pushes…..
blood through arteries between heart beats
elastic fibers consist mainly of cross-linked _________surrounded by __________microfibrils
elastin
fibrillin
elastin is synthesized in _______________and secreted as __________________monomers
fibroblasts
tropoelastin
describe the composition of tropoelastin
-long stretches of hydrophobic amino acids (GGVPPGVGV repeats)
-interrupted by more polar alanine-rich sequences containing closely spaced lysine residues
-allows formation of cross-linked network
lysines form what type of cross links
desmosine
cross-linking of ___________forms mature elastin
tropoelastin
modular protein composed of repeating tertiary surfaces related to growth factor proteins
fibrillinin
what proteins are fibrillinin related to structurally
calcium-binding epidermal growth factor (cbEGF)
transforming growth factor B1 binding protein
when are majority of our elastic fibers deposited
in utero and in the first few months after birth
what provides the scaffold for tropoelastin deposition
fibrillin
what are the steps in elastic fiber assembly
1) secretion of fibrillin monomers
-alignment of fibrillin molecules head to tail
2) secretion of globules of tropoelastin
-associate with microfibrils
-tropoelastin cross-linked by lysyl oxidase to form mature elastin
3)cross-linking of mature elastin to fibrillin microfibrils
contracted state for elasticity
-less water is associated with hydrophobic domains of elastin
-solvent is more disordered
-low energy
extended state for elasticity
-water forms ordered structures around hydrophobic peptides, which lowers the entropy of solvent
-high energy
over 70 years, elastic fibers of the ________stretch and recoil 2-3 billion times
aorta
what can cause damage to elastic fibers over time?
-matrix metalloproteinases
-oxidative damage
-additional cross-links
-mechanical stress
what protects elastin from time-dependent damage?
fibrillin
what is the mutation that causes Marfan syndrome?
mutation in fibrillin (FBN1)
what are the symptoms of Marfan syndrome?
-often tall and thin
-very long arms, legs, fingers, and toes
-often not diagnosed until late childhood
-varying symptoms
what heart disease complications are associated with Marfan syndrome?
aortic aneurysms
problems with heart valves
what bone deformities are caused by Marfan syndrome?
scoliosis
sunken or protuberant breast bone
what eye conditions are associated with Marfan disease?
retinal detachment
dislocation of lens leading to blurred vision or loss of sight
what dental conditions are associated with Marfan syndrome?
crooked teeth or teeth that are crowded together
what does Marfan syndrome normally cause with lungs?
pneumothorax
how do you test for Marfan syndrome
physical exam
family history
eye exam
echocardiogram
genetic testing
how is Marfan syndrome treated
-blood pressure management to prevent rupture of aortic aneurysm
-surgery to correct skeletal defects
what is the role of a1-antitrypsin (AAT)
-inhibits elastase secreted by neutrophils
-reduces damage to alveoli due to inflammation
what is the most widespread and severe AAT mutation
Z variant
GAG to AAG
describe what the Z variant of AAT causes
-monomers misfold, polymerize, and aggregate in the RER of hepatocytes
-decreased secretion of AAT by the liver
-may result in cirrhosis
-leading cause for pediatric end-stage liver failure and requires liver transplantation
2-5% of patients with emphysema are predisposed to the disease by defects in what?
AAT
how does smoking and AAT deficiency correlate?
-methionine 358 is required for AAT binding to its target proteases
-smoking inactivates Met358 so AAT cannot neutralize elastase
-smokers with AAT deficiency have more lung destruction and a poorer survival rate than nonsmokers with the deficiency
how can AAT deficiency be treated
-weekly intravenous administration of AAT (augmentation therapy)
-AAT diffuses from the blood into the lung where it reaches therapeutic levels in the fluid surrounding the lung epithelial cells
