Aggrecan degradation by ADAMTSs

Stable Identifier
Reaction [transition]
Homo sapiens
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Aggrecan (large aggregating proteoglycan, chondroitin sulfate proteoglycan 1) is a major structural component of cartilage, particularly articular cartilage. The core protein has over 100 chains of chondroitin sulphate and keratan sulphate giving a MWt of about 250 kDa. The core protein has 2 N-terminal globular domains G1 and G2 and a C-terminal globular G3 domain. G2 and G3 are separated by a region heavily modified with negatively charged glycosaminoglycans (GAGs). The two main modifier moieties keratan sulfate (KS) and chondroitin sulfate (CS) are arranged into two CS regions and a KS-rich region. The 15-kDa interglobular linker (IGD) between the N-terminal G1 and G2 domains is particularly susceptible to proteolysis (Caterson et al. 2000). Degradation in this region is associated with the development of osteoarthritis (Troeberg & Nagase 2012). Members of the ADAM (A Disintegrin And Metalloprotease) protein family are responsible for this cleavage (East et al. 2007, Huang & Wu 2008).

Matrix metalloproteinase (MMP) 3 was the first protease found to degrade aggrecan. It preferentially cleaves the Asn341~Phe342 bond (Fosang et al. 1991). MMP2, 7, 9 (Fosang et al. 1992), 1, 8 (Fosang et al. 1993), 13 (Fosang et al. 1996) and 12 (Durigova et al. 2011) were all found to be able to cleave this site as well as others towards the C-terminus. However, the the majority of aggrecan fragments present in synovial fluid of OA patients are cleaved at Glu392-Ala373 (numbered here according to the UniProt sequence, these residues referred to as Glu373-Ala374 in most literature) in the IGD (Sandy et al. 1992). ADAMTS5 (aggrecanase-2, Abbaszade et al. 1999) and to a lesser extent ADAMTS4 (aggrecanase-1, Tortorella et al. 1999) are primarrily responsible (Gendron et al. 2007) though the preferred cleavage sites of these are in the CS-2 domain. ADAMTS1 (Kuno et al. 2000, Rodriques-Manzaneque et al. 2002), 9, (Somerville et al. 2003), 8 (Colins-Racie 2004), 16 and 18 (Zeng et al. 2006) can also degrade aggrecan in vitro.

Catalyst Activity

metalloendopeptidase activity of ADAMTS4, 5, (1, 8, 9, 16, 18) [extracellular region]

Inferred From
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