Aggrecan degradation by MMP1,2,3,7,9,12,13

Stable Identifier
R-NUL-3814821
Type
Reaction [transition]
Species
Homo sapiens
Compartment
ReviewStatus
5/5
General
SVG |   | PPTX  | SBGN
Aggrecan degradation by MMP1,2,3,7,9,12,13
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 believed to be largely responsible for this cleavage (East et al. 2007, Huang & Wu 2008). The majority of aggrecan fragments present in synovial fluid of OA patients are cleaved at Glu392-Ala393 (numbering used here refers to the UniProt sequence, these residues often desgnated Glu373-Ala374 in literature) in the IGD (Sandy et al. 1992).
Matrix metalloproteinase (MMP) 3 was the first protease found to degrade aggrecan. It preferentially cleaves the Asn360-Phe361 bond (numbering used here refers to the UniProt sequence, these residues often desgnated Asn341-Phe342 in literature). (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 other sites towards the C-terminus.
Literature References
PubMed ID Title Journal Year
1326552 The interglobular domain of cartilage aggrecan is cleaved by PUMP, gelatinases, and cathepsin B

Hardingham, TE, Murphy, G, Last, K, Fosang, AJ, Hamilton, JA, Neame, PJ

J. Biol. Chem. 1992
8603731 Degradation of cartilage aggrecan by collagenase-3 (MMP-13)

Murphy, G, Last, K, Fosang, AJ, Knäuper, V, Neame, PJ

FEBS Lett. 1996
8216228 Fibroblast and neutrophil collagenases cleave at two sites in the cartilage aggrecan interglobular domain

Hardingham, TE, Murphy, G, Last, K, Fosang, AJ, Knäuper, V, Hamilton, JA, Tschesche, H, Neame, PJ

Biochem. J. 1993
21055468 MMPs are less efficient than ADAMTS5 in cleaving aggrecan core protein

Nagase, H, Roughley, PJ, Durigova, M, Mort, JS

Matrix Biol. 2011
1874716 Cleavage of cartilage proteoglycan between G1 and G2 domains by stromelysins

Hardingham, TE, Murphy, G, Fosang, AJ, Hamilton, JA, Neame, PJ

J. Biol. Chem. 1991
Participants
Catalyst Activity

metalloendopeptidase activity of MMP1,2,3,7,9,12,13 [extracellular region]

Orthologous Events
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