ECM Flashcards
Roles of ECM
Structural: network of proteins and polysaccharide chains that provides strength and organizes tissues; allows for diffusion of small molecules
- provides mechanical support
- forms barriers to keep cells in proper location
- scaffold for epithelia
- aqueous medium for nutrient and metabolite exchange
Signaling: regulates behavior of cells touching, inhabiting it, migrating through it
Influences:
- cell survival
-cell growth
- cell division
- cell differentiation
- morphogenesis (during development)
ECM also serves as resouviour for growth factors which bind to proteins and other molecules in matrix and can be released or not released as needed
Organization ECM
- CT composed of semi-fluid gel (ground substance) w/ embedded fibers
- Basement membranes sheet like arrangements ECM proteins underlying epithelia
2 main classes molecules in ECM
- Fibrous proteins- organize and strengthen matrix
- Glycosaminoglycan polysaccharide chains (GAGs)- form hydrating gels that resist compressive forces and allow diffusion of small molecules
ECM remodeling
ECM is not a static things; constantly remodeling via protease and protease inhibitors playing critical role in fx and dx
Fibrous proteins of ECM
Structural: Collagen, Elastin
Adhesive: Fibronectin, Lamin
Collagen
Is a superfamily, collagen I = most common; Form structure that confers tensile strength to tissues; consists of L handed triple helix w/ 3 AA per turn what wind around each other to form rope like structure; rich in glycine and proline (every third residue is glycine)
Assembly collagen molecules
Alpha chains undergo post translational modifications; selected prolines and lysines undergo hydroxylation -> intra and intermolecular cross-linkage; alpha chains self assemble in ER forming pro collagen; post secretion N and C term properties clipped off -> individual collagen molecules assembling into fibrils -> fibrils strength via cross-links btwn lysines some collagen fibrils aggregate into collagen fibers
Collagen post translational modifications
Select proline and glycine undergo hydroxylation allowing self assembly of 3 pro-alpha chains this = necessary for inter and intra molecular cross linking; Vit C= cofactor
Formation of collagen fibril
- Synthesis of pro alpha chain
- Hydroxylation of selected prolines and lysines
- Glycosylation of selected hydroxylysines
- Self assembly of 3 pro-alpha chains
- Pro collagen tripple helix formation
- secretion
- cleavage of propeptides
- Self-assembly into fibril
- Aggregation of collagen fibrils to form collagen fiber
Scurvy
defect in post translational modification of collagen because vit C deficiency; can -> poor wound healing, bone fractures, loose teeth, bleeding
G. Pigs and primates don’t synthesize vit C
Collagen Alpha chains
mixed and matched to make different kinds of structures; fibrillar and network forming
Fibrillar collagens
long rope like fibers; fibril associated collagens help organize the fibers
Network forming collagens
Basement membranes
Anchorning- anchor basement membranes to underlying tissue
Fibrillar collagen I
bones/ skin
Fibrillar collagen II
defining cartilage of cartilage
Fibrillar collagen V
tendon
fibrillar associated collagens
bind to surface of fibrillar collagens linking them to one another and to other components of ECM; triple stranded helices of these are interrupted by non-helical domains to confer flexibility
Type IV collagen
network forming collagen; major collagen of basement membrane; flexible structure b/c interruptions to triple helical structure, interact via uncleaved terminal domains to assemble into flexible sheet like network
Collagen type VII
anchoring collagen anchor basement membranes to underlying CT; effect in this = dystrophic epidermolysis bulls (epithelial lining peels off forming mechanical trauma)
Collagen and wound healing
Fibrilar collagens form major portion of CT at repair sites; impaired collagen synthesis interferes with wound healing
Fibrosis
excessive collagen deposits
Elastin
allows tissue to stretch and recoil
critical for arteries, lung, and skin
composed of elastin molecules covered with sheath glycoprotein microfibrils
Elastin structure
composed of alternating segments of hydrophobic and alpha helical regions
- hydrophobic segments responsible for elastic properties
- helical segments form cross-links btwn adjacent elastin fibers
Prevention of tissue tearing
elastic fibers interwoven with inelastic collagen to limit extent of stretching
Fibronectin
glycoprotein
mediates cell matrix interactions contributes to organizing the matrix
most abundant ECM adhesive protein
fibronectin structure
dimer composed of similar but non-identical polypeptide chains
distinct domains allow for interaction w/ other ECM constituents and PM proteins such as integrins
Lamin
fibrous protein organizes basement membrane organizes shape synthesized first has diff binding sites for diff cell surfaces; w/o lamina no BM formed at all
Kitty with thin skin that spontaneously tears
biopsy showed abnormal collagen
- no hx of steroid use
Glycosaminoglycans
withstand compressive forces
allow rapid diffusion of nutrients, metabolites, and hormone between blood and tissues
glycosaminoglycan structure
unbranched polysaccharide chains, form hydrating gels
composed of repeating disaccharide chains that are too stiff to fold into globular units, chains = highly negative b/c sulfate or carboxyl groups on sugar = v hydrophilic = makes them resistant to compressive forces and allows rapid nutrient diffusion
Hyaluronic acid
simplest glycosaminoglycan, major polysaccharide component of ECM
Present in all tissues and body fluid v important in joints as major constituent synovial fluid; allows jt to resist compressive forces
Acts as space filler facilitating cell migration during morphogenesis and tissue repair
Hyaluronic acid structure
regular repeating sequence can be up to 25,000 units long; no sulfate groups; neg charge bc carboxyl group on flucouronic acid; not linked to core protein
Proteoglycan structure
Glycosominoglycan; long unbranched GAG chain covalently linked to core protein; several diff core proteins and # and type of attached GAG chains variable; modification of sugar residues allows for diversity; classified by sugar (Chondrotin sulfate, keratan sulfate, dermatan sulfate, Heparan sulfate); v heterogeneous
Proteoglycan associates
associated with each other, HA, fibrous proteins to form complex composits
Proteoglycans function
- For gels act as sieves regulate passage of molecules by size and charge (for gels of varrying pore size and density)
- Multiple signaling roles
- bind signaling molecules, control rate of diffusion, rate of action, and lifetime of secreted signaling molecules
- Can also directly modify activity of these signals
- Storage site for growth factors? - Cell surface proteoglycans act as coreceptors
Aggrecan
major proteoglycan of articular cartilage; 100 GAG chains attached to serine rich core protein and chondroitin sulfate and keratan sulfate chains -> hydrating gel structure -> load bearing properties and allows for diffusion of nutrients
Osteoarthritis
impaired synthesis of proteoglycan components
CKCS valve dx
bc too much proteoglycans (mitral valve dx)
Basement membrane
specialized form of ECM formed by specific interactions among type IV collagen, laminin, nidogen, and perlecan; they underlie virtually all epithelia and form thing, though flexible sheets of proteins and polysaccharides
Laminin structure
heterotrimer compost ot 3 long-polypeptdide chains held together by disulfide bonds; has diff functional domains allowing interactions w/ type IV collagen (fibrous protein), perlecan (glycosaminoglycan), nidogen(fibrous protein); self assembles through head group interaction; forms felt-like sheet
Basement membrane function
underly all epithelial cells and surround some non epithelial cells
mechanical connection btwn epithelium and underlying CT
Control of epithelial growth and differentiation
primary determinants of architecture of epithelial organs
scaffold for tissue regeneration when epithelial tissues injured
serves as selective barrier to cell movement and molecular filter (glomerulus)
Cell interaction with ECM
via matrix receptors especially interns and transmembrane proteoglycans
integrin structure
transmembrane heterodimers consisting of alpha and beta subunits; link to cytoskeleton; large N-terminal extracelluar domain binds specific sequences of ECM proteins such as fibronectin, small cytoplasmic C-term domain connects to actin cytoskeleton via talin
ECM and wound healing
- scaffold allowing restitution of cell architecture
- spatial organization of components of neuromuscular junction
Bladder issues what type mutation
Collagen Type IV
integrein on cell membranes
present in higher numbers on cell membrane, bind ligands with low affinity; strong adhesions depend on clustering of multiple integrins
integrin inactive state
integrein adopts tightly folded globular structure
integrin active state
- upon ligand binding intracellular domain opens up to reveal talin-binidng site allowing for linkage to cytoplasm
- can be activated from inside-out when cytoplasmic tail binds talin extracellular domain is pushed into active conformation that can bind components of ECM
cross talk
considerable cross talk between integrins and other signaling pathways
anchorage dependence
most cells do not grow or proliferate unless they are attached to ECM so that cells only survive and proliferate in appropriate environments (therefore integrins influence cell survival and proliferation)
integrin defects
implicated in variety of genetic dx; play role in development of cancer, autoimmune dx, and certain infectious dx
integrins recruit
intracellular signaling proteins at sites of cell-substratum adhesion
integrins vs other signaling receptors
Similarities: Differences:
-Cell surface receptor - structural linkage to
-Activates intracellular cytoskeleton
signaling molecules -Bind ligand with lower affinity
-higher concentration on cell
surface
-inside-out signaling
