19. Biochemistry | Fibrous Proteins - Collagen and Elastin

What is the primary amino acid sequence motif in collagen?

Repeating Gly-X-Y sequence where Gly = Glycine (smallest AA), X = Proline, Y = Hydroxyproline or Hydroxylysine

What is an α-chain in collagen and what structure does it form?

A polypeptide called the pro-alpha chain; three α-chains form a triple helix (tropocollagen)

How is the collagen triple helix stabilized?

By extensive inter-chain hydrogen bonds and disulfide bonds; there are no intra-chain hydrogen bonds

What types of supramolecular assemblies can collagen form?

Collagen can form fibrils, sheets, or 3D networks depending on the tissue and collagen subtype

Which enzymes perform hydroxylation of proline and lysine residues in collagen?

Prolyl hydroxylase and Lysyl hydroxylase

Which cofactor is required for collagen hydroxylation?

Vitamin C (ascorbic acid)

Which amino acid is glycosylated during collagen synthesis?

Hydroxylysine (only) is glycosylated

What occurs during synthesis of the pre-pro alpha chain?

The polypeptide contains a N-terminal signal sequence that directs it into the rough ER for translation

What occurs during formation of the pro-alpha chain?

The signal sequence is cleaved; proline and lysine are hydroxylated (vitamin C-dependent) and hydroxylysine is glycosylated via enzyme Lysyl hydroxylase (+ Vitamin C) and prolyl hydroxylase

How is procollagen formed from pro-alpha chains?

Three pro-α chains assemble into a triple helix stabilized by inter-chain hydrogen bonds and disulfide bonds

What happens to procollagen after secretion into the extracellular matrix?

N- and C-terminal propeptides are cleaved by procollagen peptidase to form tropocollagen; H-bond INTERchains stabilize triple helix - no INTRAchains

How do collagen fibrils assemble?

Tropocollagen molecules self-assemble in staggered arrays to form fibrils

How are collagen fibrils cross-linked into mature collagen fibers?

Lysyl oxidase (Cu2+-dependent) catalyzes oxidative deamination of lysine to allysine, enabling cross-links

Which enzyme is responsible for collagen breakdown?

Collagenase, a member of the MMP (Matrix Metalloproteinase) family

Which diseases are associated with Type I collagen?

Ehlers Danlos Syndrome (EDS) and Osteogenesis Imperfecta

Which diseases are associated with Type III collagen?

Ehlers Danlos Syndrome (EDS), type IV

Which disease is associated with Type XI collagen?

Stickler Syndrome

Which diseases are associated with Type IV collagen?

Alport Syndrome and Goodpasture Syndrome

What is the function of collagen compared to elastin?

Collagen provides tensile strength and structural integrity; elastin provides elasticity and recoil

What is the primary amino acid sequence of collagen?

Gly-X-Y- (Gly-Pro-HydroxyPro/HydroxyLys)

What is the primary amino acid sequence of elastin?

V-A-G-hP- (Val, Ala, Gly + some Pro; no hydroxylysine)

What post-translational modifications occur in collagen versus elastin?

Collagen: hydroxylation of Pro and Lys + glycosylation of hydroxyLys; Elastin: Lys oxidized to allysine, no Lys hydroxylation

What is the secondary structure of elastin?

Hydrophobic globules connected by hydrophilic α-helices

What type of cross-linking is characteristic of elastin?

Desmosine cross-links formed via lysyl oxidase

What is the biochemical defect in Scurvy?

Vitamin C deficiency leads to decreased hydroxylation of proline and lysine, resulting in poor collagen assembly and cross-linking

What are the clinical features of Scurvy?

Poor wound healing, prolonged bleeding, fragile blood vessels, gingivitis

What is the biochemical defect in Ehlers Danlos Syndrome?

Collagen type I/III/V defects or lysyl hydroxylase deficiency

What are the clinical features of Ehlers Danlos Syndrome?

Hyperextensible skin, joint hypermobility, bruising, and possible lethal vascular complications

What is the biochemical defect in Osteogenesis Imperfecta?

Type I collagen mutation where glycine is replaced by a bulky amino acid, leading to poor collagen packing

What are the clinical features of Osteogenesis Imperfecta?

Multiple fractures, bone fragility, blue sclera, hearing loss; severity varies by type

What is the biochemical defect in Osteolathyrism?

Lysyl oxidase is inhibited by osteolathyrogens, preventing collagen cross-linking

What are the clinical features of Osteolathyrism?

Soft or deformed bones, weak muscles; commonly linked to famine or malnutrition

What is the biochemical defect in Menkes Disease?

Copper deficiency or malabsorption leads to reduced lysyl oxidase activity and poor collagen cross-linking

What are the clinical features of Menkes Disease?

Floppy baby (hypotonia), kinky hair, developmental delay, weak bones

What is the biochemical defect in Stickler Syndrome?

Type XI collagen gene defect (also types II and IX)

What are the clinical features of Stickler Syndrome?

Flat face, myopia, hearing loss, cleft palate, joint problems

What is the biochemical defect in Marfan Syndrome?

FBN1 mutation leads to defective elastin microfibrils

What are the clinical features of Marfan Syndrome?

Tall stature, long limbs, aortic aneurysm, scoliosis, flexible joints

What is the biochemical defect in Emphysema?

α1-antitrypsin deficiency s/p E342K mutation and oxidation of M358 causes unopposed elastase to destroy alveolar elastin

How does smoking worsen Emphysema?

Cigarette smoke oxidizes methionine 358 in α1-AT, weakening its binding to elastase and increasing elastin destruction

What is the mnemonic for remembering Ehlers Danlos Syndrome?

EDS = stretchy skin (elastic like 'Dan's skin')

What is the mnemonic for remembering Osteogenesis Imperfecta?

OI = brittle bones ('I' = Imperfect bones)

What is the mnemonic for remembering Scurvy?

Scurvy = Vitamin C deficiency ‚Üí bleeding gums

What is the mnemonic for remembering Menkes Disease?

Menkes = kinky hair due to ↓ Cu2+ and ↓ lysyl oxidase

What is the mnemonic for remembering Marfan Syndrome?

Marfan = Mr. Lincoln (tall, long limbs) + aortic aneurysm

What is the mnemonic for remembering Emphysema?

Emphysema = elastin degraded by elastase due to ↓ α1-AT

Where is Type I collagen found?

Skin, tendon, bone, cornea, dentin

What is the function of Type I collagen?

Provides resistance to tension

Where is Type II collagen found?

Cartilage, intervertebral disc (nucleus pulposus), vitreous humor

What is the function of Type II collagen?

Provides resistance to pressure

Where is Type III collagen found?

Blood vessels, skin, uterus, fetal tissue, granulation tissue

What is the function of Type III collagen?

Provides structural maintenance in expansible tissues

Where is Type V collagen found?

Interstitium

What is the function of Type V collagen?

Participates in type I collagen function

Where is Type XI collagen found?

Cartilage and vitreous humor

What is the function of Type XI collagen?

Participates in type II collagen function

Where is Type IV collagen found?

Basal lamina (basement membranes)

What is the function of Type IV collagen?

Supports epithelial cells and filtration

Where is Type VIII collagen found?

Beneath stratified squamous epithelium

What is the function of Type VIII collagen?

Not clearly stated in notes

Where is Type X collagen found?

Cartilage growth plate (hypertrophic and mineralizing cartilage)

What is the function of Type X collagen?

Links to the extracellular matrix (ECM)

Where is Type IX collagen found?

Cartilage

What is the function of Type IX collagen?

Binds various proteoglycans and associates with type II collagen

Where is Type XII collagen found?

Tendons, ligaments, and some other tissues

What is the function of Type XII collagen?

Interacts with type I collagen

Where does synthesis of pre-pro-α chain occur?

Cytoplasm → Rough ER

Where does pro-α chain formation occur?

Rough ER

Where does procollagen formation occur?

Rough ER

How does secretion of procollagen occur?

Exocytosis

Where does tropocollagen formation occur?

ECM

Where does fibril assembly occur?

ECM

Where does cross-linking into collagen fibers occur?

ECM

An adult comes into a primary care clinic to establish care. He states that he has a connective tissue disorder that does something to his blood vessels, which makes them prone to rupture. Assuming that this is a type of Ehlers-Danlos syndrome, what type of collagen is likely deficient?

A. Type 1 collagen

B. Type 2 collagen

C. Type 3 collagen

D. Type 4 collagen

E. Type 5 collagen

C

The correct answer is type 3 collagen (C). Type 1 collagen (A) defects cause osteogenesis imperfecta. Type 2 collagen (B) is involved in cartilage formation. Type 4 collagen (D) is not involved in the pathology of the vascular type of Ehlers-Danlos syndrome. Type 5 collagen (E) defects cause the skin hyperextension and joint hypermobility subtype of Ehlers-Danlos syndrome.

A 2-year-old child presents with blue sclerae and a history of multiple bone fractures with minimal trauma. Genetic testing reveals a glycine-to-bulky-residue substitution in collagen type I. What is the most likely consequence of this mutation?

A. Impaired collagen cross-linking
B. Inhibited hydroxylation of lysine residues
C. Inhibition of elastase activity
D. Defective triple helix formation due to poor packing
E. Disruption of desmosine formation

D

This is osteogenesis imperfecta type I. Glycine (smallest amino acid) is required for tight packing of the collagen triple helix. Substitution with a bulky residue disrupts helix formation, causing brittle bones.

• A. Impaired cross-linking – Seen with lysyl oxidase deficiency (Menkes or osteolathyrism).

• B. Inhibited hydroxylation – Seen in scurvy due to vitamin C deficiency.

• C. Inhibition of elastase – Related to emphysema, not OI.

• E. Desmosine – Cross-links elastin, not collagen.

A 17-year-old male presents with hyperextensible skin and joint hypermobility. His brother died from a ruptured aortic aneurysm at age 22. Which of the following collagen types is most likely defective?

A. Type I
B. Type II
C. Type III
D. Type IV
E. Type XI

This is vascular Ehlers-Danlos syndrome, caused by type III collagen deficiency (important for blood vessels).

• A. Type I – Skin, bone, tendon; defective in classic OI.

• B. Type II – Cartilage, vitreous humor; Stickler syndrome.

• D. Type IV – Basement membranes; Alport and Goodpasture syndromes.

• E. Type XI – Cartilage; Stickler syndrome.

A researcher creates a knockout mouse lacking lysyl hydroxylase. Which of the following steps in collagen synthesis would be most directly impaired?

A. Removal of N- and C-terminal propeptides
B. Triple helix stabilization through disulfide bonding
C. Hydroxylation of lysine residues in the rough ER
D. Conversion of tropocollagen into collagen fibrils
E. Exocytosis of procollagen into the extracellular matrix

C

Lysyl hydroxylase hydroxylates lysine residues on pro-α chains in the rough ER. This is required for interchain hydrogen bonding and triple helix stabilization.

• A. – Performed by extracellular procollagen peptidases.

• B. – Stabilization by disulfide bonds occurs at the C-terminus.

• D. – Collagen fibril formation occurs extracellularly with lysyl oxidase.

• E. – Exocytosis is independent of lysyl hydroxylase.