Proteoglycans and Glycoproteins

Differentiate between Proteoglycans and glycoproteins.

Proteoglycans

• Protein core

• Glycoaminoglycan chains (w/ repeating disaccharides)

Glycoproteins

• Protein core

• Ogliosaccharide (no repeat disacc.)

How are complex carbs built?

• Monosaccs are added one at a time to growing carb.

• Needs to be nucleotide activated form ie most freq w/ UDP (also can be GDP or CMP, see in pic)

• Nuc activated form is specific for a given monosacc

How is glucose used for complex carb synthesis and what pathways does it go through?

Describe glycotransferases?.

• Catalyzes addition of monosaccs to other molecules

• Specific for given monosacc

• Hydrolysis of nuc linkage provides energy for formation fo the glycosidic bond

What are glycoaminoglycans(GAGs)?

• Repeating disacc units of a acidic sugar (glucuronic or iduroninc acid) and N acetylated amino sugars

• All but hyaluroninc acid attached to protein core and syn in the golgi

• All negative charged but hyaluronic acid is sulfated

  Neg charges attract water (sponges) —> confer resilience to tissues under compression.

Describe where hyaluronic acid is found and what it is used for in the OR?

• Widespread structural glycoamioglycan in the human body

• Found in cartilage, synovial fluid, vitreous humor of the eye

• Major lube of the joints

• Ess for embryogenesis, morphogenetic, and wound healing.

• Used in eye surgery (healon) and for OA pain(intraartiuclar Synvisc injection)

What are chondroitin sulfates?

• Sulfated @ 6th or 4th position of N acetyl galactoamine

• Main GAG is aggregated in Proteoglycans —>aggregate w/ hyaluronic acid

• Most abundant GAG in humans

• Largest concentration in cartilage.

What is Dermatan Sulfate?

• Differes form chondrotin-sulfate in carboxyl orientation

• Mainly found in skin, blood vessels, and heart valves.

• Increased conc in mitral valves is associated with thickening and abnormal displacement of the valve in the L atrium of the heart (mitral valve prolapse)

What is keratan sulfate and what is it associated with?

• Only GAG w/o acidic sugar

• 2 types of KS

  KS I: linked to amide of Asn (cornea)

  KS II: linked to hydroxyl of Ser (cartilage)

Clinical: Carbohydrate sulfotransferase 6 (CHST6) deficiency —>undersulfated keratan sulfate in cornea —> muscular corneal dystrophy(cloudy cornea, vision impairment)

What is heparin and herparan sulfate associated with?

• Similar but differs in sulfation pattern (heparin more sulf)

Heparin sulfate:

• Part of Perlecan (major proteoglycans in basement membrane)

• Component of cell surface mole/receptors.

Heparin:

• Stored in mast cells

• Used as a anticoagulant (management of MI and DVT)

What is a protein which at least one GAG chain is attached?

Proteoglycans

• Either cell surface receptors or ECM molecules

• Attached to protein core via spec linkage To either hydroxy of Ser or amide of Asn

***cartilage Proteoglycans (Aggrecan)

• Highest conc of GAG, main proteoglycans (aggrecan) ~ 100

• GAG mainly chondrotin sulfates w/ some keratan sulfatates

  “Brush bottle” appearance

What is the role of GAGs in the organization of the cartilage ECM?

• Aggrecan is retained in cart ECM via non covalent interaction w/ hyaluronic acid and link protein(small glycoprotein)

• Large GAG content provides tissue w/ resilience under compression

Clinical rel: OA, RA, and SLE are accompanied by excessive degration of cartilage proteoglycans —>defective cartridge func

Describe the synthesis of proteoglycans.

1. Syn of amino sugar

   • AA derived from glucose. Glutamine provides amino group.

2. Syn of glucuronic acid (cytosol)

   • From UDP glucose via oxidation

3. Syn of core protein (ER)

• HA doesn’t require protein core for syn

4. Syn of GAG chain ( Golgi, but for HA plasma membrane)

• On trisacc links at serine and sometime asparagine of the core protein

• Glycosyltransferases —> prod growing GAG via adding UDP sugars

5. Sulfation (Golgi)

• Sulfotransferases add sulfate groups to GAG —> donor is PAPS (3 phosphoadenosyl 5 phosphosulfate)

How are these GAGs degraded?

• Taken up by the cell via endocytosis

• Transported to lysosome —.degraded by specific enzymes

Clinical tie: Deficient lysosomal degradation of GAGs —> more severe diseases (mucopolysaccharidoses - lysosomal storage dis)

What is Hunter and Hurler syndrome? What are their symptoms, causes, and treatments?

What is Sanfippo syndrome types A-D (MPSIII)? WHat is Sly syndrome (MPSVII)? WHat are their causes, treatments, and symptoms?

What are glycoproteins, what are they found in and why are they important?

• Protien within ogliosaccs attached covalentyl

• No repeating disacc units

• Much small than GAGs

Functions are wide spread:

• Cell surface recognition molecules/receptors (binding sites for pathogens)

• Blood group antigens

• ECM molecules (laminins, collagens, fibronectin)

• Plams proteins (ogliosacc chains increased solubility of proteins)

What is the difference between O and N linked oligosaccarides?

O linked

• Attached to hydroxyl group of Ser or Thr, most linear

N linked

• Attached to amide of asparagine, branched, either minor fish or complex

General rule:

• 1st protein is syn in the ER, then monosacc is nucleotide acitivated, then added via glycotransferases

  O linked

  • Bulit in Golgi

  N linked

  • Builds lipid (dolichol{side product of cholesterol syn}) in the membrane of the ER

  • Oglio precursor transferred to protein in the ER—→completed in the Golgi

What is the role of N linked ogliosaccs in lysosomal targeting of proteins?

• Delivering the lysosomal enzymes into the lysosome req phosphorylation of mannose on N linked ogliosacc of the lysosomal enzyme.

What is mucolipidosis II (I cell disease)?

• Type of lysosomal storage diseases

Deficient mannose phosphorylation on lysosomal enzymes:

• Not delivered tot he lysosome(instead are secreted)

• Macromol are not degraded (enlarged lysosome, Inclusion bodies)

What are examples of glycoproteins in the MSK?

Osteonectin

• Bone glycoproteins

• Interacts with bone mineral and collagen fibers

• Facilitates collagen fiber mineralization

Link proteins

• Cartilage glycoprotein

• Stab interaction btwn hyaluronan and aggrecan

Dystroglycan

• Skeletal muscle cell membrane GP

• Binds to laminins —>med cell attachment to adj cell membrane

Clinical rel: Defective glycoaminoglycans of dystroglycan lerads to muscular dystrophy.