proteoglycans

STRUCTURE - Core protein + long, negatively charged GAG chains (repeating disaccharides: an amino sugar [GlcNAc or GalNAc] + a uronic acid [glucuronate or iduronate], except keratan sulfate, which has galactose). Most GAGs are sulfated, giving a high negative charge density. - GAGs: chondroitin sulfate, dermatan sulfate, heparan sulfate, heparin, keratan sulfate, hyaluronic acid. - Hyaluronic acid is the exception: it is NOT sulfated and is NOT covalently attached to a core protein. It forms the backbone of large aggregates, such as aggrecan in cartilage, via link proteins. - Synthesis: the core protein is made in the rough ER. GAG chains are built in the Golgi, starting with a tetrasaccharide linker on a serine residue (xylose-galactose-galactose-glucuronate). Degradation occurs in lysosomes.

FUNCTION - Negative charge attracts Na+ and water, so tissue is hydrated and resists compression (cartilage, nucleus pulposus, vitreous humor, synovial fluid). - Aggrecan (chondroitin sulfate and keratan sulfate) is the major proteoglycan in articular cartilage. - Heparan sulfate proteoglycans (perlecan, syndecan, glypican) are in basement membranes, such as the glomerular basement membrane (GBM). They provide the negative charge barrier that repels albumin. Loss of this charge causes albuminuria in nephrotic syndrome (e.g., minimal change disease). - Heparan sulfate and heparin bind antithrombin III and enhance its inhibition of thrombin and factor Xa. Heparin is stored in mast cell granules. - Heparan sulfate also binds growth factors (FGF) and acts as a co-receptor. - Dermatan sulfate is found in skin, blood vessels, and heart valves. - Keratan sulfate is found in cornea and cartilage. Corneal transparency depends on it. - Decorin (dermatan/chondroitin sulfate) binds collagen and TGF-β.

CLINICAL CORRELATES 1. Mucopolysaccharidoses (MPS) are lysosomal storage diseases with deficient GAG-degrading enzymes, so GAGs accumulate. Features include coarse facies, hepatosplenomegaly, joint stiffness, and dysostosis multiplex, with urinary GAGs elevated. - Hurler (MPS I): α-L-iduronidase deficiency. Corneal clouding, developmental delay, and airway obstruction. Accumulates heparan and dermatan sulfate. Autosomal recessive. - Hunter (MPS II): iduronate-2-sulfatase deficiency. X-linked recessive. No corneal clouding, and aggressive behavior. Mnemonic: "Hunters see clearly (no corneal clouding) and aim for the X (X-linked)." - Morquio (MPS IVA): N-acetylgalactosamine-6-sulfatase deficiency. Keratan sulfate accumulates, causing skeletal dysplasia, short stature, and normal intelligence. - Sanfilippo (MPS III) has severe neurologic involvement with relatively mild somatic features. Heparan sulfate accumulates. 2. Osteoarthritis involves degradation of aggrecan and loss of cartilage hydration, which reduces resistance to compression. Chondroitin sulfate and glucosamine supplements have not shown convincing benefit. 3. Nephrotic syndrome: loss of the heparan sulfate charge barrier in the GBM leads to selective albuminuria (e.g., minimal change disease). 4. Heparin therapy: heparin accelerates antithrombin III activity. Reversal uses protamine sulfate. HIT is a complication. 5. Aging and photoaging change GAG content in skin and cartilage.

HIGH-YIELD COMPARISON - Proteoglycan: core protein with many GAG chains (bottle-brush shape), mostly carbohydrate. - Glycoprotein: protein with short, branched oligosaccharides, mostly protein by weight. - Collagen provides tensile strength. Proteoglycans provide compressive resistance and hydration.

ASSOCIATED TERMS: aggrecan, perlecan, syndecan, decorin, hyaluronan, link protein, ECM, I-cell disease (defective mannose-6-phosphate tagging, which is a different mechanism but also a lysosomal disorder).