Lecture 27: Fibrous Proteins, Proteoglycans and Glycoproteins Flashcards
Fibrous proteins: Types and function
Types
1) Collagen fibers
2) Elastin fibers
Function:
-Structural support of surrounding cells
Proteoglycans
- Contain Glycoaminoglycins (GAGS) > Proteins
- Formed intracellularly by O-glycosylation at the core protein (in the golgi) and released into ECM
Function:
Fills the extracellular space and attract water
Collagen’s
function
Function:
-Forming of fibrils and of networks
Collagen:
Type I
Type III
Type I: Skin, bones, tendons, blood vessels, cornea
Type III: Blood vessels, fetal skin
Collagen in tendons (what do they look like)
Bundled in long and cross-linked parallel fibers.
neat looking
Collagen in bones
-Provides the overall structure and strength
and the flexibility to resist mechanical sheer
-Calcium phosphate around fibrils
Collagen Structure and Amino acid composition
Structure:
- Triple-helix of three Alpha-chains (1000 amino acids long)
- Rigid rope-like structure
- Covalently cross linked
Amino acid composition:
1) Glycine= 3rd positon
2) Proline and hydroxylproline (Hyp) have kinks = tight winding (Hydroxyl proline (OH) stabilizes collagen and needs vitamin C to function)
3) Hydrogen bonds stabilize the structure (Non covalent)
Scurvy
- Due to vitamin C deficiency
- Decreased stability and tensile strength of collagen
Symptoms:
-Bleeding gums, hemorrhages and poor wound healing
Collagen Synthesis
Collagen = insoluble
-Needs to be synthesized as soluble prcollagen before release into the ECM
Steps to synthesis:
1) Nucleus releases collagen genes
RER:
2) Synthesizes collagen as soluble procollagen
3) Postranslational modifications (hydroxylations of some proline and lysine) (NEEDS VITAMIN C)
4) Chaperone proteins connect the correct 3 pro-a-chains
Golgi:
5) Finishing glycosylation and assorting procollagen for release into ECM (Creates triple helix)
ECM:
8)
- Tropocollagen assembles into fibrils with a staggered pattern (Cuts ends)
- Covalent cross-linking in ECM needs LYSYL OXIDASE which modifies lysine residues and (NEEDS COPPER)
Biosynthesis of Collagen Type I
1) Two genes are expressed: COL1A1 and COL1A2 which lead to
2) Two pro-a1 chains and one pro-a2 chain: (a12a2) for the triple helix.
Post-translational modifications:
3) Hydroxylation of selected proline and lysine residues (vitamin C)
4) Glycosylation of selected hydroxylysine residues.
Chaperone proteins function
- Form trimers
- Help form zipper-like triple-helix formation of procollagen from the C- to the N- terminus
(Ex: Hsp 47 aka serpin)
Extracellular cross-linking
-Strengthens collagen fibers
Lysyl oxidase:
1) oxidatively removes lysine or hydroxylysine residues
2) Needs copper as cofactor and forms aldehydes = ALLYSINE or HYDROXYALLSINE residue
(Highly reactive, binds covalently to other lysine hydroxyallysine residues)
-aldehyde is highly reactive and forms a covalent bond with other lysine or hydroxylysine residues of another collagen molecule
Ehlers-Danlos syndrome:
Vascular form
Classical form
- Connective tissue disorder
- Mutation of collagen Type III and V collagen
-Hereditary enzyme deficiency of one of the enzymes
needed for collagen synthesis
Vascular form:
- Mutation of Type III
- Fragility of skin and vascular vessel walls
- Severe: lethal arterial rupture
Classical Form: -Mutation of Type V collagen Symptoms: 1) Hypermobility of the joints 2) Hyperextensibility of the skin
Osteogenesis Imperfecta (OI)
-Brittle bones disease
Cause:
-Usually inherited by mutation in one allele of the COL1A1 or COL1A2 gene (Collagen type 1 and 2 formation)
Effects on structure:
- Displacement of glycine in bone collagen
- Improper formation and stability of the collagen triple-helix
Osteogenesis Imperfecta (OI)
Types
Type I:
- Mildest form
- Bone fractures in childhood
- Hearing loss in adulthood
- blue sclerae
Type II:
- More severe
- death in utero or neonatal death bc of respiratory problems (Ex: Underdeveloped lungs/small and fragile ribcage)
Types III and V:
-Can result in scoliosis, bone malformations,
and dentiogenesis imperfecta
Elastin Fibers
-Contain elastin and microfibrils
-Allows the flexibility of blood vessels, lungs,
ligaments and skin
Elastin structure
- Hydrophobic region: rich in glycine, valine and proline.
2. Hydrophilic region rich in lysine and alanine.
Elastin and Marfan’s syndrome
- deficiency of fibrillin-1 gene (FBN1) on chromosome 15, which leads to abnormal elastic fibers.
- Elastin gene itself is normal but elastin cannot be efficiently cross-linked and the abnormal fibrillin is found in elastic fibers.
(3 allysine (lysyl oxidase) and one lysine residue are covalently linked in desmosine)
Where is Procollagen formed?
In fibroblasts, osteoblasts or chondroblast
Elastic fibers
Components:
1) Elastin
2) Microfibrils
Can be stretched and then reform without an obvious energy source
O-glycosylation
1) The first sugar is linked in the RER.
2) Enzymes, Glycosyl transferase bound in the Golgi membrane recognize the structures and link the correct additional sugars directly to the growing glycoproteins. The different oligosaccharides are often branched.
3) The first sugar is linked to the OH-group of a SERINE, THREOINE, or hydroxylysine residues
- Used for the glycosylation of proteoglycans, mucins, glycoproteins and blood group substances.
N-glycosylation
1) Formation of a mannose-rich oligosaccharide
bound to the lipid dolichol pyrophosphate.
2) This mannose-rich precursor is linked in one step
only to the nitrogen of an ASPARAGINE side chain.
3) All proteins receive the same oligosaccharide
and only later the sugars are individually modified
in the RER and Golgi dependent on the protein.
3) Complex glycoproteins or high-mannose
glycoproteins are formed in the Golgi.
4) Golgi: Transport for release into blood, cell membrane, or into lysosomes.
*Transport into lysosomes need the mannose 6-P
marker and if deficient, it leads to I-cell disease.
Elastin Synthesis
1) Tropoelastin is secreted from fibroblasts into the ECM as a highly soluble linear polypeptide
2) The protein fibrillin-1 acts as a scaffold for the extracellular tropoelastin which has a globular shape and needs to be cross-linked in order to become the insoluble elastin.
3) Lysyl oxidase acts on lysine residues of collagen and of elastin. In elastin lysyl oxidase forms about 40 allysine residues which form covalent bonds with other
lysine or allysine residues and form desmosine which is only found in elastin
What do Desmosine and isodesmosine do?
Allows elastin to stretch and bend in any direction
3 allysine (lysyl oxidase) and one lysine residue are covalently linked in desmosine
