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Cartilage contains a variety of proteoglycans that are essential for its normal …


Biology Articles » Biochemistry » The Structure and Function of Cartilage Proteoglycans » Figures

Figures
- The Structure and Function of Cartilage Proteoglycans

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Figure 1. The structural domains of aggrecan. The aggrecan core protein is depicted with three disulphidebonded globular domains (G1-3), an interglobular domain (IGD), and attachment regions for keratan sulphate (KS) and chondroitin sulphate (CS1 and CS2). The G1 domain is composed of three functional subdomains responsible for the interaction with link protein (A) or hyaluronan (B1 and B2). The CS1 domain exhibits length polymorphism due to a variable number of 19 amino acid tandom repeats. Each repeat contains two serine residues (S) that can act as attachment sites for chondroitin sulphate.

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Figure 2. Proteolytic processing of aggrecan. Aggrecan molecules are depicted interacting with hyaluronan (HA) and link protein (LP) to form proteoglycan aggregates. Proteolytic cleavage of the aggrecan core protein generates one fragment which remains bound to HA and LP and is retained in the tissue and a second fragment which is not. The size of the retained fragment varies depending on the site of cleavage, with the smallest fragment representing the free G1 domain.

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Figure 3. The structural domains of link protein. Link protein is depicted with three disulphide-bonded domains responsible for the interaction with aggrecan (A) or hyaluronan (B1 and B2). The intact link protein may possess two (LP1) or one (LP2) N-linked oligosaccharides in its amino terminal region. Proteolytic cleavage may occur within the amino terminal region to yield a truncated link protein (LP3). Cleavage may also occur within the A domain to yield fragmented LP.

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Figure 4. The formation of proteoglycan aggregates. Newly synthesized aggrecan molecules do not interact well with hyaluronan, but require a conformational change within the G1 region to facilitate interaction. The rate of the conformational change is enhanced by the interaction of link protein (LP) with the nascent aggrecan. LP-stabilized aggregates contains densely packed aggrecan molecules which are tightly bound, whereas LP-free aggregates contain more widely spaced aggrecan which is more susceptible to dissociation.

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Figure 5. Hyaluronan synthesis. Hyaluronan (HA) is a polysaccharide consisting of repeating disaccharide units of glucuronic acid (GlcA) and N-acetyl glucosamine (GlcNAc). It is synthesized by a hyaluronan synthase (HAS) residing in the plasma membrane of the cell utilizing cytoplasmic UDP-bound monosaccharides. The growing HA chain is extruded directly into the extracellular space via a pore in the cell membrane.

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Figure 6. The consequence of HAS2 ablation in cartilage. The figure shows the femur, tibia and knee joint from transgenic mice lacking HAS2 expression in their cartilagenous tissues (HAS2-/-) and wild type mice with normal HAS2 expression (HAS2+/+). The skeletal elements have been stained with alizarin red and alcian blue to identify bone and cartilage, respectively.

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Figure 7. The structural domains of SLRPs. The core protein of decorin, biglycan, fibromodulin or lumican is depicted with two disulphide bonded domains flanking ten leucine-rich repeat (LRR) domains. Each LRR domain is composed of the sequence LXXLXLXXNXL, where L is predominantly leucine but may also be I, V, A, M, F or Y, and X may be any amino acid. In the case of decorin or biglycan, one or two chondroitin/dermatan sulphate (DS) chains, respectively, reside in the amino terminal region. In the case of fibromodulin and lumican, one to four keratan sulphate chains (KS) may reside between the LRR domains.

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Figure 8. Interaction and function of SLRPs. Decorin (open circles) and fibromodulin or lumican (solid circles) are depicted interacting with different regions of a collagen fibril to form a surface coat. The dermatan sulphate chains (DS) of decorin may self-associate to facilitate fibril-fibril interaction or may interact with TGFß sequestering the growth factor in the extracellular matrix. SLRP coat formation can impede the access of collagenases (MMP1 and MMP13) to the fibril surface and retard its degradation. In the absence of SLRPs the collagen fibril would be more susceptible to degradation and TGFß would be freely able to interact with its cell surface receptors to modulate cell metabolism.

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