1.13 ECM Flashcards
The ECM is a complex network of?
collagens, proteoglycans, hyaluronic acid, laminin, fibronectin, GAGS, proteolyctic enzymes
Functions of the ECM
- capable of dynamic remodeling
- mediates cell to cell interactions
- the presence and maintenance of an intact ECM affects the capacity of a cell to proliferate, differentiate, and to express specialized functions
- cell signaling
- inflammation
- wound healing
- cell migration
- tumorigenesis
- growth factors
- structure and support
non cellular components of ECM
water, proteins, polysaccharides
Functions of the non cellular components of ECM
DEPENDS ON LOCATION IN BODY -provides physical scaffolding for cellular constituents and initiates crucial biochemical signals required for tissue morphogenesis, differentiation, and homeostasis.
what is the ECM composed of? (4 categories and examples)
- proteoglycans (GAGs covalently linked to protein)
- fibrous (collagen/elastin) fibers- help cells attach in the appropriate locations
- multiadhesive proteins (fibronectin and laminin)
- glycoproteins (involved with glycosylation)
What is the ground substance made of? (3)
- glycoproteins
- glycosaminoglycans GAG
- proteoglycans
(not fibers)
Where is the ground substance found?
space between the cells and fibers
What are GAGs and general function?
long unbranched chain polymers of repeated disaccharides with 1 amino sugar and 1 carboxy acid (aka uronic acid)
(Glycosaminoglycans are highly polar and attract water (negative charge attracts cations eg: sodium). They are therefore useful to the body as a lubricant or as a shock absorber. GELS)
Chief function - maintain proper homeostatic environment for cells and fibrous elements
4 major classes of GAGs and their major functions
- Hyaluronan - *only non-sulfated, cell migration, wound healing, morphogenesis, embryogenesis
- Chondroitin Sulfate - *most prevalent, formation of bone, cartilage, cornea
- Heparan Sulfate - anticoagulants, release of lipoprotein lipase from capillary walls
- Ketatan Sulfate - transparency of cornea
What are proteoglycans (PGs)?
macromolecules of the cell surface or ECM that are heavily glycosylated. The basic proteoglycan unit consists of a “core protein” with one or more COVALENTLY attached glycosaminoglycan (GAG) chain(s). The carbohydrate portion forms the greater mass
what is CT characterized by/defining feature ?
an abundance of extracellular matrix with relatively few cells
7 Functions of CT
- binds structures together
- separates structures
- forms a framework and support for organs and the body as a whole
- stores fat
- transports substances
- protects against disease
- helps repair damage
What is the major structural proteoglycan found in cartilage?
Aggrecan - involved in aggregation, hyaluronan binding, cell adhesion, and chondrocyte apoptosis. contains 3 globular domains G1, G2, G3
What GAG doesnt form proteoglycans?
Hyaluronic acid
Function of collagen fibers?
strengthen and organize the ECM
function of elastin fibers?
resilience
How are PGs classified?
by their core proteins, localization and GAG composition
3 main families of PGs
- small leucine-rich PGs (SLRPs) - leucine rich structural motifs flanked by cysteine residues eg: biglycan/decorin
- modular proteoglycans - combinations of structural motifs eg: perlecan, agrin, aggrecan
- cell surface PGs - eg: syndecan
What are proteoglycan aggregates?
PGs indirectly bind by linker molecules(proteins) joining proteoglycans to hyaluronic acid to form these giant proteoglycan aggregate note there is no protein core!
The charged strands give remarkable viscosity and tensile properties
Which GAG is synthesized by enzymes on the cell surface (not post translationally modified like all other GAGs) and is the largest GAG
Hyaluronate or hyaluronic acid
Which PG is anchored in the membrane, binds to chemokines, and plays crucial role in INFLAMMATION?
Syndecan-1
when epithelia is damaged, these complexes are released and diffuse away forming a (trail) chemotactic gradient that attracts neutrophils to the site
ALSO involved in cell binding and cell signaling (co-receptor of GPCRs)
During PG synthesis, what connects a GAG to a serine in the core protein?
tetrasaccharide linker (4 sugars)
How are sugar nucleotides added in PG synthesis?
sequentially by specific glycosyl transferases
Where are the core proteins of PGs made and where does it go from there?
The RER then sent by vesicular transport to the golgi where GAGs, 4 sugars, and sulfination occurs. It is then released into the ECM by exocytosis
What happens with the exception hyaluronic acid synthesis?
Proteins made in the RER but then sugared by an integral membrane protein at plasma membrane then immediately shipped out bc it is so massive. doesnt store
Which cells systhesized PGs?
fibroblasts, chondroblasts, osteoblasts
Normal vs abnormal PG catabolism?
normal = replacement of cartilage with bone during development abnormal = arthritis, tumor
4 requirements of PG catabolism
- 3 exoglycosidases
- 4 sulfatases
- 1 acetyl transferase
- step wise removal of monosaccharides
PG catbolism steps
- endocytosis
- proteolysis
- endoglycosidic cleavage by heparanase X2
- degradation to monosaccharides and free sulfate by LYSOSOMES
why are proteins susceptible to extracelluar proteases?
due to their linear conformation, but their inhibitors keep this at low levels so most breakdown occurs through lysosomal pathways
what disease affects GAGs and lysosomal storage?
Mucopolysaccharide
what 2 types of GAGs do not accumulate and can be catabolized through alternate pathways if mucopolysaccharie is a problem?
- chondroitin sulfate
2. haluronate
4 characteristics of Mucopolysaccharide?
- enzyme deficiency generalized
- autosomal recessive or x-linked
- severe and mild forms
- not apparent at birth, needs to accumulate
