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
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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
Family of genetic connective tissue disorders
via defective collagen synthesis
Classic Type
Autosomal dominant (often de novo mutation)
COL5A1 or COL5A2 genes (type V collagen)
Type V interacts with other collagens
Joint hypermobility and hyperensemble skin
Easy bruising, thin, wide scars (cigarette paper scars)
Vascular type
Autosomal dominant
COL3A1 gene (type III collagen)
Skin, blood vessels
Thin skin, easy bruising
Rupture of large arteries and “hollow” organs
Life-threatening form of EDS.
Collegen Disease: Ehlers Danlos Syndrome (Classical)
Type V Collagen Mutation
- Autosomal dominant (often de novo mutation)
- COL5A1 or COL5A2 genes
- Joint hypermobility and hyperensemble skin
Symptoms:
- Easy bruising
- thin & wide scars (cigarette paper scars)
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
Defects in Lysosome Collagen Recycling
collagenase: first partially breaks down old collagen
- The broken collogens are phagocytosed and degraded by lysosomal enzymes
several disease via exs ↑↑↑ collagen degradation
- Rheumatoid arthritis: too much degradation of cartilage collagen
- Osteoporosis: similar but with bone collagen
Intro to Elastic Fibers
>>>> flexible than collagen
- Made by fibroblasts, also smooth muscle cells, endothelial cells, and chondrocytes (cartilage cells).
- Interwoven with collagen in mesh pattern to form a three-dimensional network.
- Prevent tearing from excessive stretching
- Present in skin, lungs, ligaments, vocal cords, spinal ligaments and especially arteries
Elastin
-
ELN gene makes the Elastin of elastic fibers (stretching/recoil)
- Secreted as tropoelastin
- Assembled into elastin fibers with crosslinking via desmosine
- Contains glycine, lysine, and proline (like collagen)
-
Mostly non-hydroxylated AA
- NO HYDroxy LYSine
- some HYDroxyPROline
- NOT glycosylated
“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
