The structure, function and turnover of aggrecan, the large aggregating proteoglycan from cartilage.
Aggrecan, the large aggregating proteoglycan from cartilage contains chondroitin sulphate and keratan sulphate attached to a multidomain protein core. It aggregates by binding to hyaluronan and this is further stabilised by a separate globular link protein. There are two structurally related N-terminal globular domains, G1 and G2, of which only G1 and not G2 is involved in aggregation. The interglobular domain joining G1 and G2 contains proteinase sensitive sequences which appear to be the key site for cleavage during aggrecan turnover. Much of the keratan sulphate and all of the chondroitin sulphate is attached to the long extended glycosaminoglycan attachment region. The function of the C-terminal G3 domain is unknown. It contains a mammalian type C lectin and complement regulatory protein motifs. These may have interactive properties that contribute to matrix organisation. There is also an alternatively spliced form with an epidermal growth factor-like motif. The carbohydrate composition of aggrecan varies with cartilage source, development and age and is heterogeneous in each sample. There is evidence of a close control of chondroitin sulphate synthesis that determines chain length and disaccharide composition and which change during development and in pathology. Monoclonal antibodies that recognise specific sequences within chondroitin sulphate chains enable some of these changes in fine structure to be detected. Progressive digestion of chains with chondroitinase AC II has provided evidence of a pattern of sulphation, with 6-sulphated disaccharides more abundant towards the protein core, although the disaccharide next to the linkage region is predominantly non-sulphated.
Hardingham
T E
TE
Kennedy Institute of Rheumatology, Hammersmith, London, UK.
Fosang
A J
AJ
Dudhia
J
J
D053674:Aggrecans; D000595:Amino Acid Sequence; D000818:Animals; D002356:Cartilage / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011508:Chondroitin Sulfate Proteoglycans / Q000737:chemistry / Q000378:metabolism / Q000502:physiology; D016326:Extracellular Matrix Proteins; D006801:Humans; D037181:Lectins, C-Type; D008969:Molecular Sequence Data; D011509:Proteoglycans / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D013329:Structure-Activity Relationship
D053674:Aggrecans; D011508:Chondroitin Sulfate Proteoglycans; D016326:Extracellular Matrix Proteins; D037181:Lectins, C-Type; D011509:Proteoglycans