MSK_MT1_TBL3 (Fibrous Proteins) Flashcards
Big Picture: Types of Connective Tissue (CT) [3]
- Embryonic/Mesenchyme CT: stem cells/ makes all CT
-
Connective Tissue Proper
- Loose CT: found beneath epithelia, covers all surfaces (inside and out), glands, and surrounds small blood vessels
-
Dense CT
- Regular: functional component of tendons, ligaments, and aponeuroses
- Irregular: surrounds organs and skin as s_hock absorber,_ mostly collagen fibers and fibroblasts
- Specialized Connective Tissue (not covered): Cartilage, Blood, Bone, hemopoietic tissue, lymphatic, adipose
Outside Cell Organization (3)
- Extracellular Matrix (ECM)
- Key Fibrous Proteins
-
Resident Cells
- Mesenchymal cells (Stem)
- Macrophages cells (Immune)
- Adipocyte cells (Fat)
- Fibroblasts cells (Make Collagen)
ECM composed of (3)
- basement membrane: thin, dense sheets that surround most animal tissues
- interstitial matrix: gel between cells* & *structures
- ground substance: jelly (with NO collogen)
Types of Fiberous Proetin found outside the cell… (4)
-
Structural
- Collagen
-
Flexible
- Elastin
- Fibrillin
-
Adhesive
- Fibronectin
- Laminin
- Karatin
-
Others
- glycosoaminoglycans
- proteoglycans
- polysaccarides
Collagen Structure
- Collagen = 42 fibrous protein genes
- 25% of total protein mass
- fibroblast synthesize & secrete in ECM
- “triple helix” structure: contains three long α- helicies
- Large amounts of proline, lysine, and glycine with repeating units of Gly-X-Z.
- Glycine is internal to the helix
- X and Z will be most likely hydroxy proline and hydroxy lysine.
Collagen Structural Components (small → big)
collagen fibril → twisting self assembly → collegen molecule (rope) → triple helix
Collagen Types
Fibrous collagens (type I, II and III), which constitute about 70% of the total body collagen, have a fibrillar structure.
Type I Collagen
- skin
- bone
- tendons
- cornea
- internal organs
Defect = osteogenesis imperfecta
Type II Collagen
- cartilage
- intervertebral discs
- vitreous humor (eye)
Type III Collagen
- skin
- blood vessels
- lymph nodes, dermis, early phases of wound repair
Defect = Ehlers-Danlos syndrome
Type IV Collagen
- basement membranes : flexible, sheet-like networks and is present within all basement membranes.
- basal lamina (beneath epithelial layer)
- lens
- cochlea
genetic defects = Alport Syndrome
Collagen Synthesis Overview: In the Nucleus
Collagen gene → DNA Synthesis → Transcription (mRNA) →
Signal Sequence Directs Growing polypeptide chain into Endoplasmic Reticulum →
Collagen Synthesis Overview: In the ER
Pre-procollagen (Translation/protein synthesis) →
Signal sequence is cleaved at ends to = procollagen α- chain →
Prolyl or Lysyl Hydroxylation (Vitamin C dependent)→
Glycosylation (galactosyl and glucosyl sugars) of hydroxy lysyl →
Disulfide bond formation by Cys side chains →
pro α- chain TO procollagen triple helix (procollagen) with nonhelical propeptides at the end
__________________________________
TRANSPORT of soluble procollagen to Golgi
Collagen Synthesis Overview: In the Golgi
Golgi packages soluble procollagen in secretory vesicles →
Secretory vesicles transport soluble procollagen to cell surface →
via special COPII vesicles, XXL
Collagen Synthesis Overview: Extracellular Space
procollagen peptidases CLEAVE procollagen → Tropocollagen →
Collagen fibril self-assembly →
Covalent crosslinking between triple helix by lysyl oxidase (COPPER dependant) →
Collagen fibers formation
Synthesis and Secretion of Collagen: Nucelus and RER
- mRNA transcribed
-
Single α-chains synthesized on rough ER ribosome
- Contain signal recognition (to bind SRP)
- makes a Pre-procollagen
- Enter ER lumen (pro-α-chains)
- Some prolines and lysines are hydroxylated by using vitamin C.
- (deficiency → scurvy)
- Some hydroxylysines are glycosylated (addition of sugar)
Collagen Synthesis in Endoplasmic Reticulum and Golgi
- RER: The 3 α-chains begin to align in zipper fashion
- Form disulfide bonds that stabilize α-chains (especially at C-terminus)
- prolyl-peptide isomerase enzymes rearrange Prolines
-
Cleavage of N-terminus = “procollogen”
- (Three α-chains combine= Triple helix formation)
Collagen Synthesis: Extracellular Modifications ( in ER)
Once outside (ECM) Collagen fibrils form:
- Tropocollagen much less soluble than procollagen
- Fibrils self assemble
-
Strengthened by lysine crosslinking via lysyl oxidase
- Requires copper (Cu+2) as cofactor
- Hydrogen Peroxide (H2O2) is the side product of rxn catalyzed by Lysyl Oxidase.
- Collagen fibers made = bundles of triple helices
Crosslinking to ↑↑↑ strength
Collegen Disease: Osteogenesis Imperfecta (Brittle Bone Disease)
- genetic autosomal dominant
- Defective collagen production, ranging in severity of osteoporosis and fractures
Type I:
- MUTATION in COL1A1 or COL1A2 genes ( code for α-chains)
- Glycine (in Gly-X-Y) REPLACED by AA w/ bulky side chain.
- collagen/elastin fibers thicken & clump = ↓↓↓ of Type I collagen
Type II (lethal in utero)
Type II and IV (>>>>> severe than type I)
Multiple, recurrent fractures with minimal trauma, blue sclera, bad hearnig, bad teeth, bony deformity and short stature.
Collegen Disease: Ehlers Danlos Syndrome (Vascular)
Type III Collagen Mutation
- Autosomal dominant: COL3A1 gene (type III collagen)
- Effects: Skin, blood vessels
Symptoms:
- Thin skin, easy bruising
- Rupture of large arteries and “hollow” organs = Life-threatening form of EDS.
Menkes Disease
X-linked recessive: Mutation in the ATP7A gene
- ATPase = intestinal copper uptake & transport
- Impaired copper absorption = deficiency = ↓ Lysyl Oxidase activity
Symptoms
- parse, brittle (‘kinky”) hair
- Low body temperature
- CNS features: hypotonia and seizures
- Poor growth and developmental delay
- Osteoporosis/fractures
- Usually fatal in childhood
Contrast with Wilson’s disease = copper excess due to defects in ATP7B gene)
Scurvy
Vitamin C Deficiency
- Vitamin C is required for hydroxylation of proline and lysine
- Scurvy = brittle collagen
- via defective pro-α-chains that NO form triple helix
- Degraded in cell (not secreted)
Symptoms:
- Fragile blood vessels (bleeding/bruising)
- Loss of teeth
- Loss of wound healing
Aging Wrinkles
- ↓↓↓↓↓↓ of elastin* and *collagen in dermis
- Also collagen/elastin fibers thicken and clump
Scleroderma (Systemic Sclerosis)
Autoimmune disorder
Caused by fibroblast activation = ↑↑↑ collagen deposition
- Stiff, hardened tissue (sclerosis)
- Skin, other organ systems involved
“the scaffold” for elastin: Fibrillin microfibrils
Fibrillin-1 = A glycoprotein the forms head-to-tail polymer fiber
- Tropoelasin binds and forms a bundle.
- Lyslyl oxidase make cross-links to make mature fiber
- On outside of elastin fibers
Elastin Disease: Emphysema
Autosomal co-dominant disease of α1-Antitrypsin (AAT)
-
Imbalance between elastase (destroys elastin) and elastase inhibitor AAT (protects elastin)
- elastase breaks down Elastin
- Elastase activity is is stopped by enzyme AAT
Mutation= exs ↑ elastin DEGRADATION
- AAT = misfold & aggregate in RER of hepatocytes → ↓↓↓ AAT secretion = ↑↑↑ Excessive breakdown of elastin
- Emphysema = Lung damage
- Common in Cacasians of Northern European ancestry
Williams Syndrome or Williams-Beuren Syndrome
Partial deletion of long arm of chromosome 7 (includes gene for elastin)
Symptoms:
- Elfin appearance
- intellectual disability
-
Supravalvular aortic stenosis (narrowing)
- poor construction of ascending aorta above (aortic valve)
- High prevalence among children with WS
- Histology: Loss of elastin
Marfan Syndrome
Genetic Disorder of CT (Fibrillin)
- Mutations in FBN1 gene (chromosome 15) that codes for fibrillin-1 = Abnormal fibrillin
Symptoms
- Classic appearance: Tall with long wingspan, Pectus Excavatum (sunken chest)
- Extremities: Hypermobile joints, long fingers & toes.
- early onset Cataracts and dislocation of lens.
Adhesive Proteins
Glycoproteins that join and organize the ECM and link cells to the ECM
- Fibronectin is the adhesive protein in connective tissues.
- Laminin is the principal adhesive protein in epithelial tissues.
fibronectin or laminin LINK proteoglycans and collagen to each other + to a cell’s surface
Keratin
- homologous protein with filamentous (fibrous) structure
- expressed in epithelial cells and in epidermal derivatives such as hair, nail, and horn.
-
α-keratin : polypeptide chain, typically high in alanine, leucine, arginine, and cysteine, that forms a right-handed α-helix.
- Stabilized by hydrogen and disulfide bonds.
Fibronectin
- composed of a dimer linked by disulfide bonds near their C-termini (V shape)
- Attaches cells to all matrices EXCEPT type IV (laminin)
- Multimodular structure composed of FN-I, FN-II, and FN-III.
- The primary sequence of fibronectin connected to integrin is a tripeptide Arg-Gly-Asp.
Basement Membrane & Laminin
laminin molecules self-assemble & form networks that bind to T_ype IV collagen_
Its globule domains bind with ECM & cell surface receptors, thus linking cells = Basement Membrane (right below ECM)
Laminin
- composed of three chains (α, β, γ) arranged in the shape of an asymmetrical cross (merosin)
- coiled-coil domains joing the 3 chains into the cross heterotrimeric structure called merosin.
Defects in Laminin
- Junctional epidermolysis bullosa (JEB) = defects in Laminin 5 OR 6
- Epidermolysis: rare diseases that cause fragile, blistering skin by even minor injury
Structure of α- Keratin in Hair
