Direct activation of human neutrophil procollagenase by recombinant stromelysin

Knäuper, Vera; Wilhelm, Scott M.; Seperack, Peter K.; DeClerck, Yves A.; Langley, Keith; Osthues, Anja; Tschesche, Harald

doi:10.1042/bj2950581

Cited by 149 publications

(109 citation statements)

References 39 publications

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“…MMP-3 is a known activator of several proMMPs including collagenases (184)(185)(186), and the combined proteolysis of a trypsin-like serine proteinase and MMP-3 is required to generate fully active MMP-1 (187). MMP-3 activation of procollagenases is important in the initiation of collagenolysis (188) PC target sequence (RXKR or RRKR) between their pro and catalytic domains; this can result in secretion of active MMPs.…”

Section: Serine Proteinases and Activation Of Procollagenases In Cartmentioning

confidence: 99%

Emerging roles of serine proteinases in tissue turnover in arthritis

Milner

Patel

Rowan

2008

Arthritis & Rheumatism

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Section: Serine Proteinases and Activation Of Procollagenases In Cartmentioning

confidence: 99%

Emerging roles of serine proteinases in tissue turnover in arthritis

Milner

Patel

Rowan

2008

Arthritis & Rheumatism

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“…The serine proteinase plasmin is a known activator of several proMMPs, including proMMP-1 (collagenase 1), proMMP-13 (collagenase 3), and proMMP-3 (stromelysin 1) (18)(19)(20)(21). MMP-3 itself can activate other proMMPs, including proMMP-1, proMMP-8 (collagenase 2), proMMP-9 (gelatinase B), and proMMP-13 (22)(23)(24)(25).…”

mentioning

confidence: 99%

Inhibition of furin‐like enzymes blocks interleukin‐1α/oncostatin M–stimulated cartilage degradation

Milner¹,

Rowan²,

Sf³

et al. 2003

Arthritis & Rheumatism

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Objective. To investigate the role of furin-like enzymes in the proteolytic cascades leading to cartilage breakdown and to examine which collagenase(s) contribute to collagen degradation.Methods. Bovine nasal cartilage was stimulated to resorb with the addition of interleukin-1␣ (IL-1␣)/ oncostatin M (OSM) in the presence or absence of a furin inhibitor, Dec-RVKR-CH 2 Cl, or selective matrix metalloproteinase 1 (MMP-1) inhibitors. Collagen and proteoglycan levels were determined by assay of hydroxyproline and sulfated glycosaminoglycan, respectively. Collagenase and gelatinase activity were measured using 3 H-acetylated collagen and gelatin zymography, respectively.Results. The addition of Dec-RVKR-CH 2 Cl to stimulated cartilage reduced the release of collagen fragments and the levels of active collagenase and MMP-2, suggesting that furin-like enzymes are involved in the cascades leading to activation of procollagenases. At MMP inhibitor concentrations that selectively inhibit MMP-1, no inhibition of collagen release was observed, but increasing the concentration to the 50% inhibition concentration for MMP-13 resulted in a 50% blockage of collagen release. The addition of Dec-RVKR-CH 2 Cl to resorbing cartilage also partially blocked proteoglycan release, thus demonstrating a role for furin-activated enzymes in the pathways leading to proteoglycan degradation. Conclusion.Furin-like enzymes are involved in cascades leading to activation of procollagenases and degradation of collagen. MMP-13, which can be activated by furin-processed membrane-type 1 MMP-1, appears to be a major collagenase involved in collagen degradation induced by IL-1␣/OSM. Furin-like enzymes also appear to play a role in the pathways leading to proteoglycan degradation. These findings are of importance when considering proteinase inhibition as a target for therapeutic intervention in arthritic diseases.

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“…Activation of the procollagenases involves proteolytic and autoproteolytic cleavages within the propeptide domain, which effects the removal of the 'Pro-Arg-Cys-Gly-ValPro-Asp' sequence motif, thereby expelling the free Cys residue of the propeptide from the co-ordination sphere of the catalytic zinc ion [5][6][7][8][9][10]. The active collagenases cleave the interstitial collagens type I III with different k cli JK M values into characteristic 3/4 and 1/4 fragments and slowly hydrolyse other substrates such as cartilage aggrecan, serpins, denatured collagen and small synthetic peptide substrates [11,12].…”

Section: Introductionmentioning

confidence: 99%

Analysis of the contribution of the hinge region of human neutrophil collagenase (HNC, MMP‐8) to stability and collagenolytic activity by alanine scanning mutagenesis

Knäuper¹,

Docherty²,

Smith³

et al. 1997

FEBS Letters

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Analysis of the hinge region of neutrophil collagenase by alanine scanning mutagenesis revealed that this sequence motif has a pronounced effect on the stability and collagenolytic activity of the active enzyme. The mutagenesis of the amino acid residues in the P^ ' position of the two autoproteolytically cleaved peptide bonds (Leu 43 and He 248 ) to Ala showed that the mutant enzymes were more resistant to autoproteolysis. However, these mutants were not completely stable and autoproteolysis occurred mainly at the Ala 239 -Ile 240 peptide bond and the half-life of the active enzyme was increased by 50%. In contrast, mutagenesis of Pro 247 -> Ala (P, of the minor cleavage site Pro 247 -Ile 248 ) lead to increased susceptibility of the enzyme to autoproteolysis. However, when the other Pi position Gly 242 was altered to Ala no effect on stability was observed. The analysis of the ability of the mutant active enzymes to hydrolyse 14 C-type I collagen was assessed and our results demonstrate that the hinge sequence motif of neutrophil collagenase is important for collagenolytic activity. The alteration of the Gly 24 -Leu-Ser-Ser-Asn-ProIle-Gln-Pro 247 sequence motif to Gly 242 -Ala-Ala-Ala-AlaPro-Ala-Ala-Pro showed that the collagenolytic activity was reduced by 68.4%. In addition, mutagenesis of the downstream sequence motif Pro 7 -Thr-Gly-Pro-Ser-Thr-Pro-Lys-Pro s to Pro 247 -AIa-Ala-Pro-Ala-Ala-Pro-Ala-Pro 258 had an even more marked effect on the collagenolytic activity, which was reduced by 87.4%. When the Pro residues in the hinge motif (Pro 247 , Pro 250 , Pro 253 and Pro 256 ) were altered to Ala the collagenolytic activity dropped to 1.5% of the value observed for wild-type enzyme.

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Direct activation of human neutrophil procollagenase by recombinant stromelysin

Cited by 149 publications

References 39 publications

Emerging roles of serine proteinases in tissue turnover in arthritis

Emerging roles of serine proteinases in tissue turnover in arthritis

Inhibition of furin‐like enzymes blocks interleukin‐1α/oncostatin M–stimulated cartilage degradation

Analysis of the contribution of the hinge region of human neutrophil collagenase (HNC, MMP‐8) to stability and collagenolytic activity by alanine scanning mutagenesis

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