Fibrous Proteins

Question 1

What are the basic components of the extracellular matrix?

Answer 1

Fibrous proteins and proteoglycans

Question 2

What are fibrous proteins?

Answer 2

Include collagen fibers and elastin fibers which provide structural support of surrounding cells

Question 3

What are the functions of proteoglycanns?

Answer 3

Fill the extracellular space and attract water

Question 4

What are the functions of collagen?

Answer 4

These are forming fibrils and forming networks

Question 5

What types of collagen form fibrils? Where are each found?

Answer 5

Type 1- skin, bone, tendon, blood vessels, cornea

Type 2- cartilage, intervertebral disk, vitreous body

Type 3- blood vessels, fetal skin

Question 6

What are the types of collagen that forms networks ? Where are they located?

Answer 6

Type 4- basement membrane

Type 7- beneath stratified squamous epithelium

Question 7

What is the most abundant fibrous protein?

Answer 7

Collagen

Question 8

Briefly describe collagen

Answer 8

A typical collagen molecule is a triple helix of three alpha chains which are about 1,000 amino acids long. This rigid rope-like structure can be covalently cross-linked

Question 9

What are the functions of fibrillation collagens?

Answer 9

Provide mechanical strength

Collagen in tendons- is bundled in long and cross-linked parallel fibers

Collagen in bones- provides the overall structure and strength and the flexibility to resist mechanical sheer.
Calcium phosphate is deposited in and around the collagen fiber. The collagen gaps are nucleation sites for hydroxyapatite

Question 10

What is the distinct amino acid composition of collagen?

Answer 10

1. Glycine with the smallest side chain is found in each third position
2. Proline and hydroxyproline (Hyp)residues are abundant and forms “kinks” in the polypeptide chain which facilitates tight winding

Question 11

Explain the stabilization the collagen triple Helix

Answer 11

• Hydrogen bonds between the three a-chains stabilize the triple helix
• the bonds are formed between the peptide bonds and side chains of glycine, proline and hydroxyproline
• Hydrogen bonds are non-covalent and it is important to involve the bonds formed with hydroxyproline residues

Question 12

How are hydroxyproline residues formed for collagen?

Answer 12

Formation of hydroxyproline residues in pro-a-chains needs vitamin C

1. Done by prolyl hydroxylase (needs Vit. C)

Hydroxyproline residues are needed for collagen stability

Question 13

How are lysine residues hydroxylated ?

Answer 13

Hydroxylation of lysine residues in pro-a-chains needs vitamin C

Done by lysyl hydroxylase - needs vitamin C

Hydroxylysine residues are needed for O-glycostlation leading to the large variety of collagen molecules

Question 14

What happens to collagen that don’t have hydroxyproline?

Answer 14

Collagen without hydroxyproline residues is in stable

The collagen triple helix is normally intact up to 40 Degrees Celsius . Without hydroxyproline most of the collagen triple helix content is lost at human body temperature

Question 15

What does deficiency of vitamin C lead to?

Answer 15

Decreased stability and tensile strength of collagen leads to:

Bleeding gums, hemorrhages, and poor wound healing

Vit. C deficiency leads to scurvy

Question 16

Ddehat is special regarding collagen synthesis?

Answer 16

Collagen is an insoluble protein and needs to be synthesized as Soluble pro collagen before release into the ECM.

Pro collagen has propeptides and is formed in fibroblasts, osteoblasts or chondroblasts

Question 17

Outline collagen synthesis

Answer 17

1. Genes for pro-a1 and pro-a2 chains are transcribed into mRNAs
2. mRNA is translated on the rER into prepro-a chains that are extruded into the lumen of the rER,where the signal sequence is removed, converting prepro to pro
3. Selected proline and lysine residues are hydroxylated
4. Selected hydroxylysine residues are glycosylated with glucose and galactose.
5. Three pro-a chains assemble. Intrachain and interchain disulfide bonds form at the C-terminal propeptide extension
6. A triple helix is formed, and pro collagen is produced.
7. The procollagen molecule is secreted from a Golgi vacuole into the extracellular matrix
8. The N-terminal and C- terminal propeptides are cleaved by procollagen peptidases , producing tropocollagen (comeback to text after)

5.

Question 18

Summarize the biosynthesis of collagen type 1

Answer 18

1. Two genes are expressed: COL1A1 and COL1A2 which lead to
2. Two pro-a1 chains and one pro-a2 chain: (a1(2)a2) for the triple helix

Post translational modifications:
3. Hydroxylation of selected proline and lysine residues (vitamin C)

4. Glycosylation of selected hydroxylysine residues

Question 19

What heat shock proteins are needed in collagen synthesis?

Answer 19

HSP47 (Ser pin) are needed to form the correct trimers and for zipper-like triple helix formation of procollagen from the C- to the N- terminus

Question 20

What is the function of lysyl oxidase?

Answer 20

Extracellular cross-linking strengthens collagen fibers.

• Lysyl oxidase oxidatively deaminates lysine or hydroxylysine residues
• Lysyl oxidase needs COPPER as cofactor and forms aldehydes known as allysine or hydroxyallysine residue
• The aldehyde is highly reactive and forms a covalent bond with other lysine or hydroxylysine residues of another collagen molecule.

Question 21

What are the collagenopathies?

Answer 21

1. Ehlers-Danlos syndromes (EDS)

2. Osteogenesis imperfecta (OI)

Question 22

What is Ehler’s Danlos syndrome?

Answer 22

A large group of connective tissue disorders when can result from:

• Mutation of a collagen gene which affects often collagen type III or collagen type V
• Hereditary enzyme deficiency of one of the enzymes needed for collagen synthesis

Question 23

Describe the vascular form of EDS

Answer 23

Caused by defects in type 3 collagen and leads to fragility of skin and vascular vessel walls. It is the most severe form as it is associated with potentially lethal arterial rupture

Question 24

Describe the classical form of Ehlers-danlos

Answer 24

The classical of EDS is mostly caused by defects in type V collagen

Patients show the following:

• Hypermobility of the joints
• Hyperextensibility of the skin

Question 25

Summarize general OI

Answer 25

Brittle bone disease is caused in over 90% of patients by an autosomal dominant inherited mutation in one allele of the COL1A1 or COL1A2 gene. This results often in the displacement of glycine in bone collagen and affects the formation and stability of the collagen triple helix OI type 1 is the mildest form OI type 2 is the most severe form

Question 26

Highlight OI type 1

Answer 26

Mildest form and most common Osteogenesis imperfecta tarda Leads in early childhood to long bone fractures after minor trauma - In adulthood less fractures - Normal or near normal height - Possibility of hearing loss in adulthood - Individuals often have blue sclera. This results from a thin sclera revealing the appearance of the uveal tissue (pigmented layer)

Question 27

Highlight OI type II

Answer 27

Most severe form Osteogenesis imperfecta Congenita - Leads to death in utero or neonatal death due to respiratory problems - Can include: underdeveloped lungs and an abdominal small fragile rib cage

Question 28

Contrast collagen and elastic fibers in fibrous proteins

Answer 28

Collagen is the most abundant fibrous protein which represents 30% of total body protein mass. It forms fibrils or mesh-like networks Elastin has a highly cross-linked insoluble amorphous structure. It is the major protein in elastic fibers which allow the flexibility of blood vessels, lungs, ligaments and skin Fibrous proteins have increased collagen, and decreased elastin

Question 29

What do elastic fibers consist of ?

Answer 29

Elastin and microfibrils They can be stretched and then reform without any obvious energy source

Question 30

What is the structure function of elastin?

Answer 30

Elastin has alternating domains of: -hydrophobic region: region rich in glycine, valine, and proline -Hydrophilic region: region rich in lysine and alanine The stretched structure of elastin exposes the hydrophobic region of water. When the stretching force stops elastin reforms to its original form

Question 31

Summarize the synthesis of elastin

Answer 31

- Tropoelastin is secreted from fibroblasts into the ECM as a highly soluble linear polypeptide (about 700 amino acids) - There is only one gene for tropoelastin but different splicing of RNA leads to different isoforms - 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 - 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

Question 32

What are the functions of desmosine and isodesmosine?

Answer 32

Characteristic of elastin and allows it to stretch and bend in any direction Yellow color 3 allysine (Lysyl oxidase) and one lysine residue are covalently linked in desmosine

Question 33

What are the main characters of Marfan syndrome?

Answer 33

- long limbs - arachnodactyly - lens dislocation - aortic root dilation - Abnormal formation of rib cage

Question 34

Describe Marfan syndrome

Answer 34

Autosomal dominant syndrome hereditary defect in gene that encodes for fibrillin- 1 (FBN1) on chromosome 15 This leads to abnormal elastic fibers

Question 35

Collagen and elastin for the skin are used in…

Answer 35

Cosmetics