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Collagenases and aggrecanases: understanding the role of non-catalytic domains in cartilage matrix breakdown
Arthritis Research & Therapy volume 7, Article number: S11 (2005)
Degradation of cartilage matrix, which mainly consists of collagen fibrils and aggrecan, seriously impairs the function of joints. The primary cause of this process is elevated proteolytic enzymes. Collagen fibrils are degraded by a group of matrix metalloproteinases (MMPs) including collagenases (MMP-1, MMP-8 and MMP-13), gelatinase A (MMP-2) and MT1-MMP (MMP-14). Aggrecan is degraded by MMPs and 'aggrecanases' belonging to the ADAMTS family. Inhibitors of these metalloproteinases are considered as potential therapeutic agents to protect cartilage degradation, and many active site-directed inhibitors with a zinc-chelating moiety have been developed. Unfortunately, those compounds have serious side effects possibly due to lack of selectivity . In the hope of developing new types of inhibitors we have been investigating the mechanisms of action of collagenases and aggrecanases.
Collagenases are unique as they can degrade triple helical interstitial collagens into three-quarter and one-quarter fragments, a crucial step for collagenolysis in the tissue. Typical collagenases consist of a catalytic domain and a hemopexin domain that are connected by a linker peptide. Both domains are essential for collagenolysis. The three-dimensional structure of a prototypic collagenase, collagenase 1 (MMP-1), however, indicated that the active site of the enzyme is too narrow to accommodate triple-helical collagen. We have recently shown that collagenase locally unwinds triple helical collagen before it hydrolyses the peptide bonds . Based on a series of mutagenesis we predict that the collagen binding site is created by both the catalytic and the hemopexin domains. This potential collagen binding groove is partially blocked by the prodomain in the zymogen of MMP-1 (proMMP-1), explaining its inability to bind to collagen unless it is activated. Overall proMMP-1 has a 'closed' configuration in contrast to the 'open' configuration of the active MMP-1. The exact mechanism of how collagenase unwinds collagen is under investigation.
Another key collagenase is MT1-MMP. It is highly expressed in rheumatoid synovial lining cells invading into the cartilage. Overexpression of recombinant MT1-MMP in COS7 cells in vitro degrade reconstituted type I collagen films. This reaction requires dimerisation of the enzyme on the cell surface through the hemopexin domains. When dimerisation of MT1-MMP is prevented by overexpression of the membrane-anchored MT1-MMP hemopexin domain, the collagenolytic activity was blocked, but not its general photolytic activity.
Among 19 ADAMTSs in humans, six have been shown to have aggrecanase activity. Their non-catalytic domains include one disintegrin, one or more thrombospondin, one cysteine-rich and one spacer domain. Full-length ADAMTS-4 (aggrecanase 1) is active on aggrecan only, but when the C-terminal spacer domain is deleted it expresses broader proteolytic activity and digests fibronectin, fibromodulin, decorin and biglycan, as well as maintaining aggrecanase activity . Further deletion of the cysteine-rich and thrombospondin domains greatly reduces both activities .
These studies suggest that activities of collagenases and aggrecanases will be attenuated by inhibitors or antibodies that interact directly with their non-catalytic ancillary domains (exosite/allosteric inhibitors). Such molecules will be attractive for therapy as they will be highly selective because they are based on the unique mechanism of each proteinase.
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This work was supported by grants from the Wellcome Trust, Cancer Research UK, the Arthritis Research Campaign and the Nation Institutes of Health (USA).
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Nagase, H., Visse, R., Kashiwagi, M. et al. Collagenases and aggrecanases: understanding the role of non-catalytic domains in cartilage matrix breakdown. Arthritis Res Ther 7, S11 (2005) doi:10.1186/ar1517
- Collagen Fibril
- Cartilage Matrix
- Collagenolytic Activity
- Collagen Binding