Extracellular matrix/histology Flashcards
interstitial fluid
A complex aqueous soup of ions, proteins, proteoglycans, and signaling molecules that surrounds normal cells.
Extracellular Matrix
Composed of interstitial fluid and all surround matrix that make up the surrounding environment. Contains fibrous proteins and proteoglycans.
Extracellular function
provides shape/structure to interstitial space, lubrication and cushioning, provides anchor point for cell adhesion, allows communication between cells and controls life cycle.
ECM protein that provide structure and attachment
Collagen fibers, elastin, fibronectin
ECM that prevent compression?
GAG’s such as hyaluronic acid, chondronitin sulfate, dermatin sulfate, heparan sulfate, keratin sulfate.
Collagen
Major protein of ECM and 30% of protein mass in body. Many different collagen that differ in function, distribution, and organization. Two types: Fibrillar and nonfibrillar.
Collagen structure.
Each protein has unique left-handed helix with three amino acids per turn (Gly-X-Y) glycine, proline, hydroxyproline. Glycine compose the middle of protein and proline/hydroxyproline are on the outside that provide support.
Tropocollagen
three helical collagen proteins come together to make a triple-stranded right-handed super-helical Quaternary structure.
Fibrillar Collagen
Formed from mixture of collagen types that provides tensile strength to skin, tendons, and ligaments. Long overlapping of tropocollagen
Non-fibrillar collagen
Basement membrane collagen (type 4). Has interrupted tropocollagen. Interacts with fibrillar to form mesh-like structures.
Basement membrane
Thin layer of ECM of type 4 collagen that surrounds tissues to create barrier. Main purpose is to prevent migration of certain cell types.
collagen Synthesis
Preprocollagen is synthesized with a signal directing it to the lumen of the ER. Removal of signal results in procollagen. Post-transnational modification in the ER (proline converstion, attach sugar to protein, disulfide bonds incorporated). Disulfide bond formation triggers triple helical formation (tropocollagen). Transported to golgi and exocytosed. Converted to mature collagen by proteolysis and then can crosslink to form insoluble collagen.
Scurvy
Vitamin C deficiency via collagen synthesis.. VitC is a cofactor of hydrolase enzyme that produce hydroxyproline from proline.
Hydroxylase
convert proline to hydroxyproline in collagen synthesis. Occurs in ER.
Glycosylation
Attaches sugars to procollagen in ER.
Osteogenesis Imperfecta (brittle bone)
Point mutation in genes coding for alpha 1 or alpha 2 collagen chains. Changed amino acid sequence prevents formation of helical structure.
Elastin
Forms elastic fibers in blood vessels, lungs, ligaments, and skin. Single protein and has little post-translational modification.
Desmosine
Elastin monomers cross linked to form two dimensional latticework allowing for stretching in two dimensions.
Fibronectin
ECM protein that is attachment point for other cellular and ECM components. Many isoforms that are both tissue and developmental specific. Involved in cell adhesion, migration, embryonic morphogenesis, and cytoskeletal/ECM organization.
Proteoglycans
Gel-forming portion of the ECM sometimes known as ground substance. Contains protein chains with large amount of complex carbohydrates called glycosaminoglycan (GAG). Main role to provide support to tissue ( cartilage and connective tissue). Prevent compression stress due to large negative charge.
Glycosaminoglycan (GAG)
May contain up to 100 sugars per chain with specific repeating sequences composed of uronic acid and amino sugar. They are polyanionic due to uronic acid and high levels of sulfation on the amino sugars.
Major proteoglycans of EMC
Hyaluronic acid, Chondroitin sulfate, Dermatan sulfate, Heparan sulfate, Keratan sulfate…..all are GAG’s.
Where are proteoglycan constructed?
In the golgi apparatus. Receives protein core from ER.
mucopolysaccharidosis
Disruption of degradation and synthesis at the point of the many enzymes involved in the processes.
Aggrecans
Large macro-molecule composed of different proteoglycans that includes other extracellular proteins.
Function of proteoglycans
Large negative charge in ECM leads to numerous counterions to neutralize charge. Charge leads to water influx resulting in stiffness of ECM by binding interactions with proteoglycans and collagen. High charge allows rigidity, flexibility, and resist compressibility. Joints to withstand torsion and shock.
Hyaluronic Acid
Longest polysaccharide GAG that doesn’t have protein core and no sulfation. Major lubricating of synovial fluid and vitreous humor.
Chondroitin sulfate
Most common GAG, major component of cartilage. Resist compression of cartilage through electrical charge repulsion. Loss of causes osteoarthritis.
Dermatan Sulfate
Higher charge density than other proteoglycans, similar to chondroitin sulfate. Disruption of dermatan sulfate synthesis lead to many mucopolysaccharidosis.
Heparan Sulfate
Higher charged of all proteoglycans by mass. Major component of basement membrane. Binds many soluble regulatory proteins (interferon, GF. antithrombin). Anticoagulant properties.
Keratan Sulfate
Most heterogeneous GAG. Three types: 1-cornea hydration, 2-primarily skeletal tissue including bone/cartilage, 3-found in brain.
What is the extra cellular matrix?
It acts like reinforced concrete support for tissues. Collagen fibers act as the rebar providing strength and support. Proteoglycans act as an amorphous cement to tie everything together and provide rigidity.
Matrix Metalloproteases (MMP)
A whole class of functional proteins responsible for digesting the structural components of extra cellular matrix. MMP are synthesized as zymogens and are secreted or membrane bound.
What metal do all MMP require as a cofactor?
Zinc.
Domains for MMP’s
Propeptide domain, catalytic domain, haemopexin-like C-terminal domain
Catalytic domain
MMP domain that binds zinc and allows proteolytic activity. Activates a water molecule that is able to react with the amide bond of protein substrate and allow proteolytic reaction.
Haemopexin-like C-terminal domain
Sometimes absent from from MMP’s and may bind tissue inhibition MMP to inhibit activity.
Propetide domain
Zymogen portion of enzyme.