Extracellular matrix: Last one!! Flashcards
2 main functions of ECM
- Scaffold for cells
2. Regulating cell functions (survival, differentiation, migration, proliferation, shape)
Who secretes ECM macromolecules?
Fibroblasts and their friends (chondroblasts, osteoblasts)
4 major classes of ECM molecules
- Glycosaminoglycans (GAGs)
- Fibrous proteins: collagen and elastin
- Multidomain adapter proteins: fibronectin and laminin
- water and many solutes
How are proteoglycans formed?
Structure?
GAGs covalently linked to proteins. High molecular weight.
“Core protein” has tetrasaccharides attached to serines for the primer for polysaccharide assembly
GAG - structure & function
Structure: large, unbranched disaccharide polymer. Contain an AA sugar (usually sulfated) and a sugar group substituted with a carboxy group (acidic sugar). NEGATIVELY charged
Function: due to neg charge and solubility, they can aggregate together and fill large volumes by forming gels.
Common GAGs
hyaluronan, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate
Fibrous proteins (2 types) - structure & function
Collagen:
- Most abundant proteins in mammals (25%)
- 25 subunits forming 20 different collagens
- Collagen I most abundant - connective tissue
- Collagen IV - basal lamina
- Provide tensile strength in connective tissue
Elastin:
- Elastic protein found in many tissues, forms networks
Multidomain adapter proteins (2 main types) - structure and function
General: Act as binding sites for other matrix macromolecules
Fibronectin:
- 2 large subunits linked by S-S bond
- subunits have functionally distinct binding domains
- Type III fibronectin repeat binds integrins & contains Arg-Gly-Asp sequence
- highly insoluble fibronectin fibrils
Laminin:
- 3 subunits (a,b,g) form asymmetric S-S cross shape
- Found in the basal lamina only
- self-assemble via interactions between the ends of their arms
Water and solutes - function
Found in the “gel” between cells: allows for easy diffusion of nutrients and growth factors
Who breaks and remakes everything in the ECM?
Matrix metalloproteases (MMPs) & serine proteases
Quick! What are 2 types of fibrillar proteins and 2 multidomain adapter proteins
Fibrillar: Collagen & elastin
MAP: fibronectin & laminin
Role of adhesion in cell function and survival in metazoans
Adhere to each other to survive and form distinct compartments in cell.
3 types of CAMs and their ligands:
- Cadherins - homophilic binding with other cadherins
- Ig - Ig domains of Ig proteins on other surfaces
- Integrins - laminin, fibronectin, collagen
Cadherins
Cadherins:
- single-pass transmembrane glycoproteins
- found as homodimers
- extracellular domain has 5 repeats and is Ca++ dependent
- homophilic binding in a zipper-like fashion.
(Type of CAM)
Immunoglobulins (Igs)
IgSFs:
- single-pass transmembrane glycoproteins
- Homophilic binding mechanism
- Found as monomers - do not require Ca++
- Usually contain fibronectin type III domains close to membrane
(Type of CAM)
Integrins
Integrins:
- Heterodimers (alpha and beta subunits)
- Heterophilic binding
- Lots of mix-n-match for binding selectivity
- ECM-binding domain at end: binds laminin, fibronecti, collagen, etc
- can attach intracellularly on the tail: attach to catenins
(Type of CAM)
Role of CAM in signaling
- Extracellular portions of CAM interact with signal proteins to tell the cell what it’s attached to (outside-in)
- Cell can interact with CAM to chang eor get rid of its extracellular adhesion (inside-out)
What are the 3 MMPs that the jerk wants us to know? Why are they important?
MMP2
MMP9
MMP14
They are very specific for collagen 4 in basement membrane (BM)
-Key for cancer cell to extrapolate from primary tumor and breach BM (made of collagen 4)
2, 9 , 14 are the only MMPs that can digest it.
Example of ECM in disease
- Collagen 1 - skeletal dysplasias
- Fibronectin null - embryonic lethal mice
- laminin - nephrotic syndrome, NMJ issues
- MMP 2 or 13 loss - osteolysis and bone dysplasias
- Overexpression of MMP2, 9, 14 - high invasive cancer
Cell adhesion in disease
- Type I leukocyte adhesion deficit - affects a particular integrin
- Type II leukocyte adhesion deficit - affects a selectin, a CAM involved in leukocyte rolling
- Cancer - early sign of carcinogenesis is change in CAM; cadherin down regulation; anchorage independence from loss of adhesion; catenins act as tumor suppressors and so their loss leads to cancer
