Proteoglycans: structure and function

Abstract

Proteoglycans (PGs) occur predominantly in extracellular matrices and cell surfaces. Thcy consist of one or many glycosaminoglycan chains linked to protein. The glycosaminoglycans which are characteristic o f extracellular spaces include chondroitin sulphate, keratan sulphate, heparan sulphate, dermatan sulphate and hyaluronic acid ( H A ) [ I ] . Thcy are unbranched polysaccharides and all, with the exception of hyaluronate, occur in covalent linkage to protein. Their acidic nature arises from the presence of carboxylate and/or sulphate groups. T h e PGs in the extracellular matrix of cartilage have bcen the subject of much investigation and a great amount of information has become available in recent years on their molecular structure. T h e main bulk o f the tissue volume ih made up of the extracellular matrix and this consists o f a highly concentrated solution of PGs embedded in a network of type I1 collagen fibres. They can be extracted from cartilage in 4 M-guanidinium chloride in the presence of protcinasc inhibitors and purified by associative and dissociative density gradient centrifugation 121. T h e major PGs which occur in cartilage are the large, aggregating chondroitin sulphate PG and the smaller dermatan/chondroitin sulphate PGs. T h e former exists as a polydisperse structure with M , 0.5 x 10-4 x 10 D a 131. It consists of a protein core ( M , approx. 220 kDa) which is heavily substituted with chondroitin sulphate and keratan sulphate and with Nand 0linked oligosaccharides. T h e glycosaminoglycans are concentrated in domains along the protein core (Fig. I n ) . T h e keratan sulphate chains occupy a region close to the N terminus 141 and the chondroitin sulphate chains are found along a large portion of the polypeptide backbone stretching towards the C-terminus 151. T h e ability of this proteoglycan to form a strong and specific non-covalent interaction with H A (Fig. 1 h ) has been well characterized and has bcen shown to involve a globular domain at the N-terminus of the protein core [6, 71. A large number of proteoglycan monomers can bind to a single chain of HA. Doege er ul. [7a] have proposed the name 'aggrccan' to describe this structure. The resulting aggregated structure. with its very high negative-charge density, attracts a large amount of water so that it may occupy volumes that arc 30-50 times its dry weight [8]. T h e globular H A binding region ( H A B R ) binds t o a dccasaccharide or larger fragment of H A [c)]. A large number o f proteoglycans bind to a single hyaluronate chain and cach interaction is stabilized by link protein. T h e electrostatic repulsion between chondroitin chains on adjacent protco-