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128 Cards in this Set

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Name the connective tissues found in the body:
Cartilage
Bone
Tendons, ligaments
Sub-epithelial layers
(basal lamina, dermis)
What are the 3 major classes of macromolecules in connective tissue?
1. Proteins
2. Glycosaminoglycans (GAGs)
3. Proteoglycans
What are the 2 main categories of ECM Proteins? Give 2 examples of each.
-Structural - collagens, reticulin, and elastins.
-Cell binding - laminins and fibronectin
What are the 4 GAGs (Glycosaminoglycans)?
-Hyaluronans
-Chondroitin sulfates
-Heparin sulfates
-Keratan sulfates
What are proteoglycans?
Proteins with GAGs bound to them.
What proteoglycan is found in cartilage?
Aggrecan
3 types of Structural Proteins in ECM (again)
1. Collagen
2. Reticular fibers
3. Elastic fibers
What are reticular fibers?
Fibers that form a reticulum network made up from the same protein subunits as COLLAGEN.
How is reticulin different from collagen?
-Its fibers are thinner
-Network instead of aligned
-Resists forces from various directions.
What tissue are reticulin fibers important for stabilizing?
Small blood vessels and nerve twigs.
What is the name for the interwoven network of reticulin?
Stroma
What is the function of stroma?
Stabilization of parenchyma (functional cells).
What protein composes Elastic fibers?
Elastin
What is the structure of elastic fibers like?
Single wavy elastin molecules are cross-linked to form network that expands/contracts randomly.
How are elastin molecules held together?
Via covalent bonds.
Where are elastin fibers functionally important?
In joining vertebrae
What are 2 types of CELL BINDING PROTEINS in connective tissue?
1. Fibronectins
2. Laminins
How much protein in the body is collagen?
25% by mass
What are the 4 common structural elements of collagen?
1. Made of a trimer helix
2. Rich in hydroxy/proline and hydroxy/lysine
3. Glycine is the AA at every 3rd residue
4. Its native structure is a trimer
How can the collagen trimers be made up?
As homotrimers or heterotrimers
How many different gene products of collagens exist?
At least 33!!!
What is the collagen superfamily arrangement like?
There are 27 collagen types arranged in 7 classes.
What is Procollagen?
A trimeric protein secreted from cells
What is the structure of procollagen composed of?
Central: triple helical domain
Ends: globular amino- & carboxy-terminal ends (propeptides).
What is tropocollagen?
Aka, Collagen. What remains when propeptides (ends) of procollagen are removed.
What is the tropocollagen structure composed of?
Triple helix of 3 polypeptide subunits, supercoiled.
What is at the ends of the tropocollagen?
Telopeptides - these are involved in microfibril formation.
What is a collagen microfibril?
The precursor to collagen fibrils.
How do microfibrils assemble?
By self-assembly of tropocollagens into a staggared arrangement
What is the self-assembly of tropocollagens into microfibrils called?
Concatenization - head to tail w/ intervening 35 nm gap, side-side in staggard arrangement.
What does the staggard arrangement of tropocollagens achieve?
Greater stability as the electrostatic and hydrophobic interactions are maximized.
How is microfibril structure stability achieved?
Via covalent cross-linkages btwn tropocollagens.
What does the crosslinking of tropocollagens involve (chemically)?
Oxidative deamination of lysine and hydroxylysine!!
Give the actual structure of:
-Primary structure
-2ndary structure
-Quaternary structure
1' = x-y-Gly
2' = left-hand helix
4' = right-hand superhelix
Describe the 2ndary helical structure of collagen
-right handed
-3 AA per turn
-Every 3rd residue is Gly
Why is every 3rd residue gly in collagen?
Because Gly is the only residue that accomodates the unique left-hand superhelix conformation it assumes.
What type of characteristic does Collagen show on a Ramachandran plot?
Very tight, narrow area - b/c the Psi/Phi angles of the primary structure occupy a vary narrow range.
What are the 2 main areas of collagen synthesis and assembly?
1. Intracellular
2. Extracellular
What 3 things are accomplished during the intracellular phase?
1. Form single-strand helix
2. Hydroxylate/glycosylate AA's
3. Assemble triplex
What are the 4 things accomplished in the extracellular phase of collagen synthesis?
1. Cleave terminal propeptides
2. Assemble multiple collagens into a fibril
3. Covalently crosslink fibrils
4. Aggregate fibrils -> fibers
What is Step 1 of intracellular processing?
Hydroxylation of Proline
What are the requirements for proline hydroxylation?
-Ascorbate
-alpha-ketoglutarate
-Oxygen
-Fe2+
What enzyme achieves proline hydroxylation?
Prolyl hydroxylase
What is the actual proline hydroxylation reaction?
A dioxygenase reaction with 2 components:
1. Oxydative decarboxylation of alpha-ketoglutarate
2. Hydroxylation of proline
Why is ascorbate essential for collagen formation?
IT keeps the enzyme's Fe2+ in the reduced state.
What happens when ascorbate is not available?
Fe2+ is oxidized to Fe3+ and the enzyme is incapable of hydroxylating proline.
What happens when proline is not hydroxylated?
Collagen is much less stable and has a reduced melting temp
What is the Tm of collagen?
The temp at which half the proteins are unfolded.
What is a potential way to control excessive collagen synthesis?
Use inhibitors of prolyl 4-hydroxylase to inhibit synthesis.
What are the pluses/minuses of using Prolyl hydroxylase inhibitors?
Pluses: collagen specific; collagen proteins will melt at biological temp (37)
Minuses: ALL collagens unstable; accumulation and reintroduction of the enzyme causes 'crisis' of functional collagen - lifelong therapy.
What is the 2nd intracellular processing step?
Hydroxylation of Lysine.
How does lysine hydroxylation proceed?
Same manner/requirements as Proline hydroxylation.
What is the function of hydroxylated lysine?
-substrate for glycosylation
-Crosslinking
What is the function of hydroxylated proline again?
Increasing the Tm of collagen (stability).
Which positions in collagen's AA chain are held by Lys/Pro?
Gly = glycine
X - lysine
Y - Proline
In what cell compartment does lys/pro hydroxylation occur?
Both in the endoplasm. reticulum.
During post-translational modifications what else happens other than Pro/Lys hydroxylation?
O/N-glycosylation
Where does glycosylation occur?
-N glycosylation in ER
-O glycosylation in Golgi
What does N-glycosylation consist of?
Glycosylation of N atom on Asparagine side chains
What does O-glycosylation consist of?
Glycosylation of Hydroxyl groups (Ser/Thr)
How is O-glycosylation of Collagen specifically done?
Addition of Glucose/Galactose to Hydroxylysine residues.
Why does collagen get glycosylated?
Because the sugars are involved in crosslinking collagen fibers.
What is step 3 of collagen intracellular processing?
Initiation of triple superhelix formation at the C-terminal propeptides.
What is the significance of the C-terminus in the collagen protein structure that allows the triple helix formation to begin?
It is rich in Cysteine residues.
What stabilizes the three collagen chains as superhelix formation begins?
Disulfide bonds between the 3 molecules.
What is step 3 in collagen intracellular processing?
Zipping up the triple helix structure.
What direction does collagen zipping up go?
C-terminus -> N-terminus
What is the rate-limiting step in collagen synthesis?
Cis-trans isomerization of proline residues.
Which step is proline isomerization?
Step 5
Why must proline be isomerized?
Because it is the one AA residue that can exist in both cis and trans isomers.
What enzyme is responsible for catalyzing cis-trans isomerization of proline?
Prolyl isomerase
What is the 6th step in intracellular processing of collagen?
Hydrogen bonding between chains to stabilize triple helix.
Where do the H bonds occur in step 6?
Between Glycine residue Hydrogens, and C=O groups on adjacent chains.
What is step 7 of intracellular processing?
Exocytosis of the protocollagen molecule from the cell.
What does protocollagen consist of?
Core triple helix, N- and C-terminal propeptides.
What is the first step in extracellular processing of collagen?
Proteolytic cleave of N/C-terminal propeptides
What enzyme cleaves the propeptides?
Procollagen proteases - one specific for N and C-termini.
What results from the cleavage of procollagen?
Tropocollagen (mature).
What is step 2 of extracellular processing of tropocollagen?
Self-assembly into a protofibril.
What is the structure of a collagen protofibril like?
Head-to-tail, side-by-side lateral associations of helices that are staggared.
What is step 3 in extracell. processing?
Crosslinking of neighboring fibers.
How is protofibril crosslinking achieved?
By the covalent crosslinking of neighboring lysines/hydroxylines.
What is the first step in lysine crosslinking?
Converting the lysine residues to aldol form - allysine or hydroxyllysine.
What enzyme catalyzes lysine aldol formation?
Lysyl oxidase
What occurs after the initiation of lysine crosslinking?
Aldol condensation in one of 2 alternate methods.
What is the first type of lysine crosslink?
Aldol condensation of 2 neighboring allysines.
What is the 2nd type of lysine crosslinking?
Crosslinkage of Allysine and neighboring Lysine; then amadori rearrangement.
What occurs after lysine crosslinkage of mature collagen?
Aggregation of fibrils to form fibers.
What type of staining pattern do collagen fibers exhibit?
Dark and light striated patterns.
What are 3 types of collagen diseases in general?
1. Inherited
2. Dietary
3. Autoimmune
What are the 2 important human diseases associated with Collagen type 1?
-OI = Osteogenesis imperfecta
-ED = Ehlers-Danlos
What type of inheritance pattern is assoc. w/ OI?
Autosomal dominant
What are the main pathologic characteristics of OI?
-Abnormal Type 1 Collagen
-Brittle bones
-Repeated fractures at minor trauma sites.
What are the main differences between OI type 1 and 2?
Type 1 = most common, mildest. Fractures easily. Sclera blue; teeth/ossicles deformed. Collagen structure is NORMAL but decreased amt.
Type 2 = most severe, lethal at/shortly after birth. Improper collagen structure.
How specifically is collagen synthesis different in Types 1 and 2 OI?
Type 1: normal collagen, decreased amts.
Type 2: abnormal collagen.
What type of mutation is seen in OI types 1 and 2?
Type 1: null mutation in one copy of alpha-1 gene.
Type 2: subtle mutation in same.
How many alpha-1 chains must be mutated to result in non-functional collagen?
Even one is sufficient!
What is the functional result of Type 1 OI mutation?
only 50% of normal collagen produced.
What is the functional result of Type 2 OI mutation?
Only 25% of normal collagen produced, 75% of abnormal (nonfunctional) produced.
What dietary insufficiency results in collagen deficiency?
Scurvy - ascorbate (vit C) deficiency
What autoimmune disease is associated with collagen abnormality?
Bullous Pemphigoid
What is the molecular basis of bullous pemphigoid?
An autoantibody is produced against BP180; Complement is activated, Neutrophils called, Protease sereted, and Adhesion molecules cleaved.
What is the result of cleaving adhesion molecules in bullous pemphigoid?
Basal cells are detached from the dermis.
Review; the types of ECM tissue are:
-Proteins
-GAGs
-Proteoglycans
2 categories of protein:
1. Cell binding
2. Structural
2 types of cell binding proteins:
1. Fibronectin
2. Laminectin
What is the structure of fibronectin like?
-Dimeric w/ intersubunit disulfide bonds.
-6 domains (5 are binding sites for other proteins)
What component of fibronectin is the binding site for integrin?
The RGD loop
Describe the integrin-binding subunit of Fibronectin:
-7 beta sheets
-Antiparallel composition
-Disordered loop is the actual binding site.
What are laminins?
Another type of cell-binding protein
What type of structure do laminins have?
Hetero-trimer composed of alpha, beta, gamma chains.
What is the function of laminin?
To serve as binding sites for other matrix molecules.
What are the 3 types of structural proteins?
1. Collagen
2. Reticular fibers
3. Elastic fibers
What are 3 general features of collagen to remember?
1. Long, straight, unbranched.
2. Most common fiber in connective tissue.
3. Semi rigid rods
What is reticular fiber made of?
Same protein as in collagen.
How is reticular fiber different from collagen?
-Subunit arrangement and interactions are different.
-Tough but flexible
-Branches
What is the main function of reticular fiber?
Stabilization of organ vasculatures.
What are elastic fibers?
Branched, wavy fibers made of the protein elastin which serve functions like vertebral interconnection.
What are GAGs?
Glycosaminoglycans.
What are GAG structures like?
Long, unbranched chains of repeating disaccharides that undergo subsequent modifications like sulfate addition.
What is the non-sulfated GAG?
Hyaluronic acid
What are the sulfated GAGs?
-Chondroitin Sulfate
-Dermatan sulfate
-Herparan sulfate
-Keratan sulfate
What is the purpose of GAGs?
To attach to a core proteoglycan
How do GAGs attach to proteoglycans?
Via covalent links through O-glycosidic bonds, to Ser residues on the core protein.
Why do proteoglycans resemble bottle brushes?
Because the GAG's extend out and repel each other via charge repulsion.
Which GAG associates with proteoglycans?
Hyaluronic acid
What stabilizes GAG-proteoglycan assemblies?
link proteins
What is the sugar:protein ratio in proteoglycans?
Much greater than 1