proteoglycan

STRUCTURE - Core protein + many linear, negatively charged GAG chains made of repeating disaccharides (an amino sugar + uronic acid or galactose). Synthesized in the rough ER (core protein), then GAGs are added in the Golgi. Chains attach via a tetrasaccharide linker (xylose-galactose-galactose-GlcA) to serine residues (O-linked). - Sulfation (and the carboxylate groups) give a high negative charge density. This attracts Na+ and water, giving hydration, turgor, and resistance to compression. - Aggregates: in cartilage, aggrecan binds hyaluronan via link protein to form huge aggregates. Hyaluronan is the one GAG that is NOT sulfated and NOT covalently attached to a core protein (so it is not a true proteoglycan).

KEY GAGs - Chondroitin sulfate: cartilage, tendons, ligaments, aorta. Aggrecan is the main cartilage proteoglycan. - Keratan sulfate: cornea, cartilage, intervertebral discs. Corneal transparency depends on it. - Heparan sulfate: basement membranes (e.g., glomerular basement membrane, which gives a negative charge barrier against albumin), cell surfaces (syndecans, glypicans). Binds growth factors (FGF) and antithrombin. - Heparin: mast cell granules; it is an anticoagulant (activates antithrombin III) and is not a typical ECM component. - Dermatan sulfate: skin, blood vessels, heart valves. - Hyaluronic acid: synovial fluid, vitreous humor, umbilical cord (Wharton jelly), cartilage.

FUNCTIONS - Cushioning and lubrication of joints (synovial fluid, cartilage). - Compressive resistance (collagen resists tension, proteoglycans resist compression). - Filtration barrier (glomerular basement membrane: loss of heparan sulfate causes proteinuria, e.g., in diabetic nephropathy). - Sequestration of growth factors and cytokines, and cell signaling and adhesion. - Corneal transparency (keratan sulfate).

CLINICAL CORRELATES - Mucopolysaccharidoses: lysosomal storage diseases caused by deficient lysosomal enzymes that degrade GAGs. GAGs accumulate in lysosomes and are excreted in urine. - Hurler (MPS I): α-L-iduronidase deficiency. Dermatan and heparan sulfate accumulate. Features: coarse facies, corneal clouding, hepatosplenomegaly, developmental delay, gargoylism, airway obstruction, and cardiac disease. Autosomal recessive. - Hunter (MPS II): iduronate sulfatase deficiency. X-linked recessive. Similar to Hurler but with NO corneal clouding, milder course, and aggressive behavior. - Mnemonic: "Hunters see clearly (no corneal clouding) and aim for the X (X-linked)." - Osteoarthritis: degradation of aggrecan (by aggrecanases/ADAMTS and MMPs) and loss of cartilage hydration and compressive strength. - Heparan sulfate loss in the glomerular basement membrane contributes to albuminuria. - Glucosamine/chondroitin supplements: widely used for OA, but evidence of benefit is limited. - Marfan and other ECM disorders: not primary proteoglycan diseases, but cystic medial degeneration involves proteoglycan accumulation in the aortic media (e.g., Marfan, aortic dissection). - Tumor/cell biology: syndecans and other heparan sulfate proteoglycans modulate growth factor signaling and metastasis.

HIGH-YIELD TAKEAWAYS - Proteoglycan = core protein + GAGs (mostly sulfated, negatively charged, attract water). - Hyaluronan is the exception (unsulfated, no core protein). - Collagen = tensile strength; proteoglycans = compressive resistance and hydration. - GAG degradation defects (lysosomal) = mucopolysaccharidoses.