Reactome: A Curated Pathway Database

Aggrecan binds Hyaluronan and HAPLN1

Stable Identifier
R-HSA-2318623
Type
Reaction
Species
Homo sapiens
Compartment
Locations in the PathwayBrowser
Summation

In articular cartilage the major non-fibrous macromolecules are aggrecan, hyaluronan (HA) and hyaluronan and proteoglycan link protein 1 (HAPLN1). The high negative charge density of these molecules leads to the binding of large amounts of water (Bruckner 2006). HA is bound by large aggregating proteoglycans (the hyalectans). Aggrecan (ACAN) is predominantly expressed in cartilage, versican is widely distributed, while brevican and neurocan are largely restricted to nervous tissues. ACAN is ~90% carbohydrate. The core protein is highly glycosylated, mostly by the glycosaminoglycan (GAG) chains chondroitin sulphate (CS) and keratan sulphate (KS). Each ACAN molecule has ~100 CS chains of around 20 kDa and ~60 KS chains of 5-15 kDa. CS is attached to an extended domain between globular domains 2 and 3, while KS is widely distributed. The core protein also contains sites for the attachment of N-linked and O-linked oligosaccharides (Nilsson et al. 1982).

The G1 N-terminal domain of ACAN has a lectin-like binding site with high affinity for HA (Watanabe et al. 1997, Hardingham 2006). HA is a long unbranched, unsulphated GAG synthesized free from protein attachment by three HA synthases (Spicer & McDonald 1998). It has an average molecular weight of several million Da. HA content steadily rises in aging cartilage and can reach 10% of the total GAG. ACAN, HA and the small glycoprotein HAPLN1, known as Link protein, are found in huge multi-molecular aggregates comprised of numerous ACAN monomers non-covalently bound to HA, stabilized by HAPLN1 which forms a ternary complex with the G1 domain of ACAN and HA (Ratcliffe & Hardingham 1983, Grover & Roughley 1994, Kiani et al. 2002).

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