Session 7: ECM Flashcards
What are integrins?
Heterodimers that form from transmembrane proteins to act as receptors for ECM proteins
- different alpha/beta dimers recognize different ECM proteins (collagen, fibronectin, laminin)
Name the various types of proteins in the ECM.
fibrous proteins - collagens, elastin and fibrillin (BULK of ECM)
adhesive proteins - fibronectin and laminin (cell:cell and cell:matrix interactions)
gel proteins - proteoglycans (holds water for hydration)
Is the ECM organized or random?
Organized
- info. for how cells align in tissue
- hold gradient of factors to induce haptotactic migration
Explain what durotaxis is.
Durotaxis is cell migration toward higher ECM stiffness (density)
- increased capacity for deposited factors
What is the most abundant ECM protein?
Collagen - fibrous protein
Describe collagen: structure, amino acid sequence.
collagen has a distinctive repeating amino acid sequence = GLY-X-Y
- gly –> allows tight helical packing
- X and Y –> usually proline and hydroxyl proline
intra/extracellular processing controls triple helix formation (stability)
- central region similar but N- and C- termini vary –> different function
What would happen as a result of mutation in collagen gene?
Osteogenesis Imperfecta (OI) = brittle bone disease
- when collagen doesn’t properly form because of mutation –> bone matrix won’t form properly
Describe the characteristics of elastin and fibrillin
Elastin - brings stretch
Fibrillin - brings structure and allow for retraction
What effect would a mutation in fibrillin have on blood vessels?
Marfan syndrome - large arteries are weakened
- may result in aortic dissection and sudden death (heart can rupture)
- mutation causes decreased flexibility in blood vessels
- diagnosis: heart abnormality
Name the two major types of adhesive proteins.
Laminin and Fibronectin
- promote cell:cell and cell:matrix interaction
- soluble plasma fibronectin participates in blood clots
What is the amino acid sequence within laminin and fibronectin?
RGD
arginine-glycine-aspartic acid
- recognized by SOME integrin dimers
How can RGD peptide be used within chemotherapy? platelet aggregation?
Chemotherapy:
RGD peptide (mimetic) competes with RGD within ECM protein and can inhibit migration
- Lowers metastasis
Platelet aggregation:
RGD peptide inhibits platelet aggregation –> lowers blood clotting
How do disintegrins work? What could they be used for?
Disintegrins are 3 mimics of RGD and “occupy” integrins –> blocking site of cell attachment to ECM (competitive)
Application:
- disruption/prevention of cell integrin-ECM interactions
- prevent blood clotting
Explain how Eptifibatide works as a drug.
Reduces blood clots by binding to a ring formation to get rid of N- and C- termini.
Explain how Tirofiban works as a drug.
Reduces platelet clotting - peptidomimetic
- synthetic
- protein-like chain used to mimic a peptide (competitively bind to integrin –> blocks RGD)
What is one major example of a gel protein? What is its function?
Proteoglycans - proteins with sugar residues, covalently linked to R groups
- repeating disaccharide unit: GAG (ex. D-glucuronic acid and N-acetyl- D-galactosamine
- attracts positive ions bc of its negative charge
- ions attract water –> proteoglycans swell
- PG loss –> arthritis
What is the basal lamina?
The basement membrane (thin)
- good at separating compartments of tissues
- contains all 3 ECM components (collagen, laminins, proteoglycans)
How does Emphysema relate to ECM-degradation?
Caused by uncontrolled release of ECM-degrading enzymes
- ex. matrix metallo-proteases (MMPs) break down collagen; dependent on Ca2+ and Zn 2+
solution: blocking MMPs function
How does the ECM, intracellular networks, and cell motility contribute to metastasis?
- MMP degradation of collagen and other matrix proteins
- actin-based cell movement
- integrin-based cell attachment to the ECM
Explain how bat-tPA (Activase) works to break fibrin/fibronectin-based blood clots.
Activase is a recombinant human tissue plasminogen activator
- it will activate plasminogen to plasmin
- plasmin will breakdown a fibrin clot
