gaglecture09 - AfterEsko,J Proteoglycan molecules form...

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After Esko, J The Glycosaminoglycans
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Plasma membrane Proteoglycan molecule Proteoglycan complex Polysaccharide molecule Collagen Fiber Integrin Microfilaments of cytoskeleton Proteoglycan molecules form complexes by noncovalently attaching to long polysaccharide molecules Collagen fibers are embedded in a web of proteoglycan complexes Integrins are membrane proteins that are bound to the ECM on one side and to microfilaments on the cytoskeleton on the other. This linkage can transmit stimuli between the cell’s external environment and its interior. Fibronectins attach the ECM to the plasma membrane of the cell Heparan sulphate structure Components of the extracellular matrix Anionic polysaccharide chains Fibrous proteins
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Hyaluronan (HA) GlcNAc GlcA GlcNAc GlcA GlcNAc GlcA GlcNAc GlcA GlcNAc GlcA n 1000 Abundant in skeletal tissues, synovial fluid, skin, and vitreous Ovulation/ fertilization Macrophage stimulation Angiogenesis Cell migration Morphogenesis and differentiation β4 β3 β4 β3 β4 β3 β4 β3 β4 β3 After Esko, J
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Simoni, R. D. et al. J. Biol. Chem. 2002;277:e27 Karl Meyer, Columbia University
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Physical Properties Gels of high viscosity, and a great lubricant since at high shear its viscosity drops, but remains resilient Interglycosidic H-bonding restricts rotations across glycosidic bonds Promotes rapid recovery after mechanical perturbations Hydrated matrices rich in hyaluronan expand the extracellular space, facilitating cell migration. There is both a polar and a hydrophobic face for interaction with other macromolecules After Hascall and Laurent
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HA synthase(s) located in plasma membrane Copolymerization of UDP-GlcNAc and UDP-GlcA occurs independently of a core protein HA can contain 250-25,000 disaccharides (10 5 - 4x 10 7 Da, ~10 μm, the length of an erythrocyte) Half-life rate ranges from 2 weeks in synovial fluid to 5 minutes in the bloodstream After Weigel, P
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Diagram of a putative metabolic scheme for hyaluronan degradation. From Stern, R.
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Hyaluronan Binding Proteins After Esko, J
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Cartilage - Proteoglycan Aggregates Aggrecan: Large chondroitin sulfate proteoglycan present in cartilage and other connective tissues Core protein ~400 kDa ~100 chondroitin sulfate chains of ~20 kDa Hyaluronic Acid Aggrecan Forms aggregates with hyaluronic acid (HA) High charge density creates osmotic pressure that draws water into the tissue (sponge) Absorbs high compressive loads, yet resilient After Esko, J
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Kresge, N. et al. J. Biol. Chem. 2005;280:e28 Albert Dorfman, University of Chicago
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Ulf Lindahl, Uppsala University
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Golgi processing of Glycosaminoglycans
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Chondroitin Sulfate 4S 4S 4S 6S 6S GalNAc GlcA 6S Non-sulfated chondroitin is rare in vertebrates, but multiple types of sulfated chondroitins are known (A, B, C, D, etc) Multiple sulfotransferases decorate the chain The chains are easily characterized using bacterial chondroitinases which degrade the chain to disaccharides An epimerase can flip the stereochemistry of D-GlcA to L-IdoA (Dermatan Sulfate) IdoA β4 β3 β4 β3 β4 β3 β4 β3 β4 β3 After Esko, J
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