Proteoglycan degradation by the ADAMTS family of proteinases (original) (raw)
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The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family
Genome biology, 2015
The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defec...
Arthritis research & therapy, 2006
A major and early feature of cartilage degeneration is proteoglycan breakdown. Matrix metalloprotease (MMP)-13 plays an important role in cartilage degradation in osteoarthritis (OA). This MMP, in addition to initiating collagen fibre cleavage, acts on several proteoglycans. One of the proteoglycan families, termed small leucine-rich proteoglycans (SLRPs), was found to be involved in collagen fibril formation/interaction, with some members playing a role in the OA process. We investigated the ability of MMP-13 to cleave members of two classes of SLRPs: biglycan and decorin; and fibromodulin and lumican. SLRPs were isolated from human normal and OA cartilage using guanidinium chloride (4 mol/l) extraction. Digestion products were examined using Western blotting. The identities of the MMP-13 degradation products of biglycan and decorin (using specific substrates) were determined following electrophoresis and microsequencing. We found that the SLRPs studied were cleaved to differing ex...
Small leucine-rich proteoglycans and matrix metalloproteinase-14
HAL (Le Centre pour la Communication Scientifique Directe), 2019
Small leucine-rich proteoglycans (SLRPs) are important regulators of extracellular matrix assembly and cell signaling. They are a family of proteoglycans that are present in extracellular matrix and that share in common multiple repeats of a leucine-rich structural motif. SLRPs have been identified as inhibitors of cancer progression by affecting MMPs, especially MMP-14 activity. Lumican, a member of the SLRPs family, and its derived peptides were shown to possess anti-tumor activity. Interestingly, it was demonstrated recently that lumican interacts directly with the catalytic domain of MMP-14 and inhibits its activity. The aim of this review was to summarize the interactions between SLRPs and MMPs with a special interest to lumican.
Small leucine-rich proteoglycans and matrix metalloproteinase-14: Key partners?
Matrix Biology, 2017
Small leucine-rich proteoglycans (SLRPs) are important regulators of extracellular matrix assembly and cell signaling. They are a family of proteoglycans that are present in extracellular matrix and that share in common multiple repeats of a leucine-rich structural motif. SLRPs have been identified as inhibitors of cancer progression by affecting MMPs, especially MMP-14 activity. Lumican, a member of the SLRPs family, and its derived peptides were shown to possess anti-tumor activity. Interestingly, it was demonstrated recently that lumican interacts directly with the catalytic domain of MMP-14 and inhibits its activity. The aim of this review was to summarize the interactions between SLRPs and MMPs with a special interest to lumican.
Proteoglycans: many forms and many functions
The FASEB Journal, 1992
Proteoglycans are produced by most eukaryotic cells and are versatile components of pericellular and exiracellular matrices. They belong to many different protein families. Their functions vary from the physical effects of the proteoglycan aggrecan, which binds with link protein to hyaluronan to form multimolecular aggregates in cartilage; to the intercalated membrane protein CD44 that has a proteoglycan form and is a receptor and a cell-binding site for hyaluronan; to heparan sulfate proteoglycans of the syndecan and other families that provide matrix binding sites and cellsurface receptors for growth factors such as fibroblast growth factor (FGF). One feature that recurs in proteo.. glycan biology is that their structure is open to extensive modulation during cellular expression. Examples of protein changes are known, but a major source of structural variation is in the glycosaminoglycan chains. The number of chains and their length can vary, as well as their patteru of sulfation. This may result in the switching of different chain types with different properties, e.g., chondroitin sulfate and heparan sulfate, and it may also resultin the selectiveexpression of sulfated chain sequences that have specific functions. The control of glycosaminoglycan structure is not well understood, but it does appear to be used to change the properties of proteoglycans to suitdifferentbiologicalneeds. Proteoglycan forms of proteins are thus important modifiers of the organization of the pericellular and extracellular matrices and modulators of the processes that occur there.-Hardingham, T. E., Fosang, A. J. Protoglycans: many forms and many functions.
Journal of Biological Chemistry, 2016
The metalloproteinase ADAMTS-5 (A disintegrin and metalloproteinase with thrombospondin motifs) degrades aggrecan, a proteoglycan essential for cartilage structure and function. ADAMTS-5 is the major aggrecanase in mouse cartilage, and is also likely to be the major aggrecanase in humans. ADAMTS-5 is a multidomain enzyme, but the function of the C-terminal ancillary domains is poorly understood. We show that mutant ADAMTS-5 lacking the catalytic domain, but with a full suite of ancillary domains inhibits wild type ADAMTS activity, in vitro and in vivo, in a dominant-negative manner. The data suggest that mutant ADAMTS-5 binds to wild type ADAMTS-5; thus we tested the hypothesis that ADAMTS-5 associates to form oligomers. Co-elution, competition, and in situ PLA experiments using full-length and truncated recombinant ADAMTS-5 confirmed that ADAMTS-5 molecules interact, and showed that the catalytic and disintegrin-like domains support these intermolecular interactions. Cross-linking experiments revealed that recombinantADAMTS-5formedlarge,reduction-sensitiveoligomers with a nominal molecular mass of ϳ400 kDa. The oligomers were unimolecular and proteolytically active. ADAMTS-5 truncates comprising the disintegrin and/or catalytic domains were able to competitively block full-length ADAMTS-5-mediated aggrecan cleavage, measured by production of the G1-EGE 373 neoepitope. These results show that ADAMTS-5 oligomerization is required for full aggrecanase activity, and they provide evidence that blocking oligomerization inhibits ADAMTS-5 activity. The data identify the surface provided by the catalytic and disintegrin-like domains of ADAMTS-5 as a legitimate target for the design of aggrecanase inhibitors. ADAMTS-5 (TS5) is one member of a family of secreted, multidomain, zinc-dependent proteinases known as A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS). 2 TS5 is a major aggrecan-degrading enzyme (aggrecanase) (1) mediating proteolysis and loss of aggrecan from articular cartilage in arthritic diseases. TS5 inhibitors are currently in development for arthritis therapies (2, 3), although ADAMTS-4 (TS4) might also have a role in human joint disease (4-6). The most important aggrecanase activity is cleavage at the EGE 373 2 374 ALG (numbering is from 1 EEVP of the mouse mature protein (NCBI accession number Q61282)) bond in the aggrecan interglobular domain. Aggrecanases also cleave at conserved sites in the chondroitin sulfate-rich region of aggrecan, including SELE 1279 2 1280 GRGT, REEE 1467 2 1468 GLGS, TAQE 1572 2 1573 AGEG, and VSQE 1672 2 1673 LGHG (7, 8). Fragments arising from proteolysis at these sites have been detected in cartilage and synovial fluids from patients with arthritic diseases including rheumatoid arthritis, osteoarthritis, and juvenile idiopathic arthritis (9-12). TS5 is a multidomain enzyme comprising an N-terminal pro (Pro)-domain, a catalytic (Cat) domain, a disintegrin (Dis)-like domain, two thrombospondin (TS)-type 1 motifs, a cysteinerich (CysR) region, and a spacer (Sp) domain as reviewed previously (13-15). It is expressed as a zymogen that requires cleavage by pro-protein convertases (16, 17) at a polyarginine consensus sequence to remove the pro-domain. Further processing at the C terminus by autocatalysis gives rise to multiple forms of TS5, and recombinant C-terminal truncates have altered enzyme activity and substrate specificity (18, 19). The active and C terminally truncated forms of TS5 are readily detected in tissue extracts and experimental systems (20-22). Previous studies have shown that the C-terminal ancillary domains of TS4 and TS5 govern the specificity of the enzymes by modulating substrate binding (18, 19, 23) and internalization via lipoprotein receptor-related protein receptors (24, 25). The results of studies in HTB-94 chondrosarcoma cells suggest that the CysR domain helps localize TS5 in the extracellular matrix (19), whereas in TS4, the spacer domain is thought to mediate matrix binding (26-29). Hyaluronan binding to the Dis domain (20) and binding of heparan sulfate proteoglycans to the CysR *