Fibrous Proteins Flashcards
(47 cards)
1
Q
Collagen is synthesized majorly by
A
fibroblasts
2
Q
collage can also be synthesized by
A
muscle cells and epithelium
3
Q
Most common type of collagen
A
Type I Collagen
4
Q
Type I collagen chains
A
- two alpha1 chains
- 1 alpha2 chain
5
Q
Type II collagen chains
A
- three alpha1 chains
6
Q
Type I collagen Location
A
- ECM
- Loose connective tissie
- bone
- tendons
- skin
- cornea
7
Q
Describe a typical collagen molecule
A
- long, rigid structure
- three alpha- chains intertwined one to another
- rope- like triple helix Qry structure
8
Q
Type II collagen location
A
cartilage, vitreous humour
9
Q
Type III Collagen Location
A
Are really reticular fibers and have diverse distribution
10
Q
Type IV collagen location
A
Basement membrane or basal lamina
11
Q
All collagens have 3 polypeptide chains with at least…
A
one stretch of triple helix
12
Q
Non- triple helical domains of collagen
A
- non- collagenous domains
13
Q
Type IV collagen non- collagenous domain
A
- Found at Carboxy terminus
- called as NC1 domain
- forms a mesh- like structure because its large
14
Q
Alport Syndrome
A
- Mutations to the genes coding for Type IV collagen
15
Q
Goodpasture’s Syndrome (autoimmune)
A
- antibodies against the alpha 3 protein constituent of Type IV collagen
- attacks the basement membranes of
- glomeruli
- alveoli
16
Q
Collagen Structure
A
- Rich in Pro and Gly
- Repeats: Gly- X- Y
- X= any amino acid
- Y= Proline or Hydroxyproline
- 3 alpha chains
- each in a non- classic alpha- helix conformation
- Contains post- translational derivatives of Pro and Lys
- Hydroxyproline (Hyp)
- Hydroxylysine (Hyl)
17
Q
Biosynthesis of collagen: Pre- pro alpha- chains
A
- prepro-a- chains contain a signal sequence at the N- terminus that targets the polypeptide into the lumen of the rER
- signal sequence is cleaved in the rER to yield a pro- a- chain
18
Q
Biosynthesis of collagen: pro-a- chain in the rER
A
- Random selection of Pro and Lys residues contained in the pro-a- chain undergo hydroxylation
- after hydroxylation …
- Selected Hydroxylysine residues are glycosylated with glucose and galactose
19
Q
Hydroxylation of Pro and Lys residues at the rER
A
- coenzyme: ascorbic acid (Vit C)
- prolyl hydroxylase: makes Hyp
- lysil hydroxylase: makes Hyl
20
Q
Biosynthesis of collagen:
Begining of the formation of pro- collagen triple helical molecule
A
- Interchain disulfide bridge formation between 3 pro- alpha- chains
- Hydrogen bonds stbilize the triple helical conformation of pro- collagen
21
Q
Biosynthesis of collagen:
Translocation of procollagen and secretion
A
- molecule translocates to Golgi
- is packaged into vesicles
- vesicles fuse with the plasma membrane
- secreted into the ECM
22
Q
Biosynthesis of collagen: Procollagen clipping at the ECM to yield tropocollagen
A
- procollagen molecules are clipped
- C and N- terminal propeptidases
- Now is called tropocollagen
23
Q
Biosynthesis of collagen:
Tropocollagen maturation to yield mature collagen
A
- Lysyl oxydase
- aldol condensation
- Schiff base formation
- mature collagen is obtained
24
Q
ECM Lysyl Oxydase
A
- Copper requiring enzyme
- catalysis of tropocollagen into mature collagen
- performs
- aldol condensation
- Schiff base
- covalent cross- linking of collagen molecules
25
26
Summary of Biosynthesis of Collagen
* RER synthesis pre-pro-α-chain with signal sequence .
* Pre-pro-α-chain enters into lumen of RER where signal sequence is clipped (pro-α-chain), proline and lysine hydroxylation occurs.
* S-S bond formation between the pro-α-chains (initiates the winding process) to produce procollagen .
* Procollagen moves to Golgi (processing of oligosacharide chains)
* Procollagen loaded into vesicles and are secreted into ECM
* Propetidases cleave N- and C-terminal propetides convert procollagen to tropocollagen.
* Tropocollagen undergo cross-linking to form mature collagen.
27
4 diseases of abnormal collagen synthesis
1. Osteogenesis Imperfecta
2. Ehlers- Danlos Syndrome
3. Menke's Syndrome
4. Scurvy
28
Describe Osteogenesis Imperfecta
aka "brittle bone disease" or "Lobstein syndrome"
Type I collagen affected
* Mutations
* *COL1A1* : proa1 (I) chain gene
* *COL1A2*: proa2 (I) chain gene
* 90% : reduced synthesis of proa1 (I) chains
* others involve single base subsitution
* Gly---\> bulky AA= compromise the structural integrity of the molecule
29
Osteogenesis imperfecta: Clinical
* Osteopenia----\> brittle of bone
* "pop-corn like" deposits of mineral in x- rays of the long bones is an ominous sign (bad indicating)
* frequently Blue Sclera
* Dentinogenesis imperfecta
* due to lacking dentin
* progressive hear loss
* positive familial history
30
Ehlers- Danlos Syndrome (EDS)
* different types of EDS
* typically affects the joints, skin and blood vessels
* characterized by
* hypermobile joints
* hypereslasticity of the skin
31
Classic EDS I -severe
* Affected: Collagen Type V
* Mutations:
* *COL5A1*
* *COL5A2*
32
Classic EDS II: Mild
* Affected: Collagen Type I
* Mutations:
* *COL1A1*
* *COL1A2*
33
EDS III: Hypermobile EDS
* Affected: Tenascin X.
* minor component of the CT that appears to regulate the assembly of collagen fibers
* Mutation:
* *TNXB gene*
34
EDS IV: Vascular EDS
* Affected: Collagen Type III
* mutation:
* *COL3A1*
35
Ehlers- Danlos Syndrome Signs and symptoms
* Ligament and Joint changes
* laxity and hypermobility of joints
* mild to irreducible dislocation of hips and other large joints
* Skin (variable)
* thin
* velvety
* hyperextensibility "rubber person syndrome"
* cigarette- paper scars
* Easy bruise
* mitral valve prolapse and hernias
* scoliosis
* degenerative arth
36
Scurvy
* Deficiency in ascorbic acid (Vitamin C)
* required for the proper functioning of key hidroxilating enzymes:
* prolyl hydroxylase
* lysyl hydroxylase
* No stabilization of the procollagen structure
* impaired fibrillogenesis
37
Scurvy Signs and symptoms
* BLEEDING
* Skin changes with roughness
* Corkscrew hair
* petechiae
* easy bruising
* loosening of teeth
* poor wound healing
38
Menkes Disease
* X- linked genetic disease
* Mutation
* *ATP7A*
* deffective copper binding P- type ATPase
* Decreased activity of copper (Cu) dependent Lysyl oxidase
* defective collage cross- linking
39
Menkes Disease Signs and Symptoms
* Low serum Cu levels
* Deposition of Cu in intestinal cells
* Brittle hair
* growth failure
* deterioration of the nervous system
40
Elastin fibers
* integrity of CT
* found abundant in
* aorta
* ligaments
* ciliary nodules of the eye
* distensible property
41
Elastin: Biological features
* Precursor: Tropoelastin secreted into the ECM
* Lysil oxidase: Lys contained in tropoelastin is converted into allysine
* 3 allysines and 1 unmodified Lys react to form desmosine
* desmosine cross-liking yields elastin (extensively interconnected)
42
a1- antitrypsin
* Function: protects elastic tissues of the lung from destructive action of elactases.
* Inherited deficiency:
* emphysema
* cirrhosis
* Positive acute phase protein
43
Elastin and a1- antitrypsin
a1- antitrypsin protects elastin from being degraded by inhibiting the neutrophil elastase
\*Neutrophil elastase: degrades elastin of alveolar walls and other tissue proteins
44
a1- antitrypsin: biological features
* inhibits a number of proteolytic enzymes including elastases
* synthesis
* mainly: liver
* other: monocytes and macrophages
* Mutation: a1-AT gene
* Substitution: (GAG- AGG)
* Lys--- \> Glu
* mutated protein
* polymerized in the rER of hepatocytes, not secreted
45
a1- Antitrypsin (A1AT) deficiency
* autosomal RECESSIVE
* decreased function A1T1 in:
* Blood
* lungs
* increased deposition of abnormal A1T1:
* liver
* impairing liver function
* possible cirrhosis and failure
* Severe deficiency =\> panacinar emphysema (COPD)
* specially if exposed to cigarette smoke
* Symptoms:
* SOB
* wheezing
* rhonchi
46
Marfan's Syndrome
* Autosomal dominant
* Mutation: *FBN1*
* glycoprotein Fibrillin- 1
* biogenesis and maintenance of elastic fibers
* Problem:
* Affected Fibrillin-1 binds a latent form of TGFß keeping it sequestered
* inability to do function
* Reduced levels of fibrillin-1 affectinng normal function of elastin
* TGFß levels increase also inappropiate for the ECM
47
Marfan's syndrome: Clinical presentation
* Triad:
* long limbs
* dislocated lenses
* aortic root dilatation
* Skeletal:
* Arachnodactyly
* scoliosis
* pectus excavatum/ carinatum
* joint flexibility
* stretch marks
* Cardiac
* Prolapse of the mitral/ aortic valves (and signs of regurgitation)
* Signs: Cold limbs
* palpitations
* angina pectoris
* Lung: risk of spontaneous pneumothorax
