Generation and Activity of the Ternary Gelatinase B / TIMP-1 / LMW-Stromelysin-1 Complex

Kolkenbrock, Hansjörg; Orgel, Dagmar; Hecker-Kia, Adelheid; Zimmermann, Jürgen; Ulbrich, Norbert

doi:10.1515/bchm3.1995.376.8.495

Cited by 26 publications

(22 citation statements)

References 16 publications

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“…This is consistent with the theory that a ternary complex between MT1 MMP, TIMP2, and progelatinase A can form on the cell surface (17,18,37). In agreement with this, an E375A-progelatinase A⅐TIMP2 complex was able to inhibit MT1 MMP cat in a fluorimetric assay, 5 presumably due to the formation of a ternary complex as described by Kolkenbrock and colleagues (37)(38)(39).…”

Section: Discussionsupporting

confidence: 89%

The TIMP2 Membrane Type 1 Metalloproteinase “Receptor” Regulates the Concentration and Efficient Activation of Progelatinase A

Butler¹,

Butler²,

Atkinson³

et al. 1998

Journal of Biological Chemistry

545

486

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, but residues 418 -474 were not important. A similar pattern was seen using cell membrane-associated MT1 MMP; residues 568 -631 were required for binding and activation of progelatinase A, whereas residues 418 -474 were not. Neither region was required for activation in solution. The addition of TIMP2 to HT1080 membrane preparations expressing MT1 MMP, but depleted of endogenous TIMP2, resulted in potentiation of progelatinase A activation. This effect was dependent upon TIMP2 binding to MT1 MMP rather than at an independent membrane site. Together, the data suggest that TIMP2 forms a receptor with MT1 MMP that regulates the concentration and efficient generation of functionally active gelatinase A.

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Section: Discussionsupporting

confidence: 89%

The TIMP2 Membrane Type 1 Metalloproteinase “Receptor” Regulates the Concentration and Efficient Activation of Progelatinase A

Butler¹,

Butler²,

Atkinson³

et al. 1998

Journal of Biological Chemistry

545

486

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“…We have also shown that soluble aggrecanase in conditioned medium does not occur in a latent form that is activatable by exposure to APMA or trypsin. Indeed, aggrecanase activity appears to be destroyed by APMA exposure similar to that described for membrane type 2 MMP but not other members of the MMP family (23). This study has not addressed the potential of other physiological mechanisms for aggrecanase activation e.g.…”

Section: Discussionmentioning

confidence: 85%

Differential Expression of Aggrecanase and Matrix Metalloproteinase Activity in Chondrocytes Isolated from Bovine and Porcine Articular Cartilage

Hughes¹,

Little²,

Büttner³

et al. 1998

Journal of Biological Chemistry

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The release of aggrecan catabolites from cartilage is an early event in the pathogenesis of degenerative joint diseases. The enzymes involved in this process are unknown, controversial, and the subject of intense investigation. In this paper we have utilized a recombinant substrate containing the interglobular domain (IGD) of aggrecan to study specifically aggrecanase versus matrix metalloproteinase (

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“…This hypothesis is central to our current understanding of physiological activation of MMP-2 where the proMMP-2͞TIMP-2 complex is believed to inhibit MT-MMP and localize MMP-2 to the cell membrane where it is activated by membrane proteinases. However, in the case of the analogous proMMP-9͞TIMP-1 complex such involvement in cell surface activation has not been found, but proMMP-9͞TIMP-1͞Stromelysin-1 soluble ternary complex has been observed in vitro (44), proving that the inhibitory N terminus of TIMP-1 is functional in the complex. A major unsolved question in this context is how activated MMP-2 is released from the ternary complex.…”

Section: Resultsmentioning

confidence: 94%

Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2

Morgunova

Tuuttila

Bergmann

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

195

165

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Matrix metalloproteinases (MMPs) are a family of multidomain enzymes involved in the physiological degradation of connective tissue, as well as in pathological states such as tumor invasion and arthritis. Apart from transcriptional regulation, MMPs are controlled by proenzyme activation and a class of specific tissue inhibitors of metalloproteinases (TIMPs) that bind to the catalytic site. TIMP-2 is a potent inhibitor of MMPs, but it has also been implicated in a unique cell surface activation mechanism of latent MMP-2͞gelatinase A͞type IV collagenase (proMMP-2), through its binding to the hemopexin domain of proMMP-2 on the one hand and to a membrane-type MMP activator on the other. The present crystal structure of the human proMMP-2͞TIMP-2 complex reveals an interaction between the hemopexin domain of proMMP-2 and the C-terminal domain of TIMP-2, leaving the catalytic site of MMP-2 and the inhibitory site of TIMP-2 distant and spatially isolated. The interfacial contact of these two proteins is characterized by two distinct binding regions composed of alternating hydrophobic and hydrophilic interactions. This unique structure provides information for how specificity for noninhibitory MMP͞ TIMP complex formation is achieved. Matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) (also termed gelatinase A and B or 72-kDa and 92-kDa type IV collagenases, respectively) distinguish themselves from other secreted MMPs in that their latent proenzyme form can make a complex with tissue inhibitor of MMP (TIMP) (1-4). This complex has been proposed to facilitate a unique activation mechanism of the gelatinase A on the cell surface. According to the current central paradigm, which has been studied mainly for latent MMP-2͞gelatinase A͞type IV collagenase (proMMP-2), TIMP-2 first forms a complex with proMMP-2 by binding to its hemopexin domain, after which the complex localizes to the cell surface where it binds to the active site of a membrane-type MMP 1 (MT1-MMP) molecule (5-8). This ternary proMMP-2͞TIMP-2͞MT1-MMP complex then facilitates the activation of its proMMP-2 by another MT1-MMP molecule. A large body of data shows that this complex is entirely different from the inhibitory complex of TIMP-2͞active MMP-2. It is formed between the C-terminal domain of the inhibitor and the Cterminal hemopexin of MMP-2, so that both molecules maintain their proteolytic and inhibitory properties, respectively (9, 10). These noninhibitory complexes between progelatinases and TIMPs are restricted to proMMP-2 and TIMP-2, TIMP-3, or TIMP-4 on the one hand and to MMP-9 and TIMP-1 on the other. This specificity has been addressed in several earlier studies, and sequence elements on both inhibitor and proteinase critical for the specific interaction have been identified. TIMP-2 has a negatively charged C terminus, which differs from that of TIMP-1. This C terminus has been suggested to mediate specificity and kinetics of the complex formation (11-13). In contrast, the hemopexin domain of MMP-2 features a characteristic pattern of positive s...

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Generation and Activity of the Ternary Gelatinase B / TIMP-1 / LMW-Stromelysin-1 Complex

Cited by 26 publications

References 16 publications

The TIMP2 Membrane Type 1 Metalloproteinase “Receptor” Regulates the Concentration and Efficient Activation of Progelatinase A

The TIMP2 Membrane Type 1 Metalloproteinase “Receptor” Regulates the Concentration and Efficient Activation of Progelatinase A

Differential Expression of Aggrecanase and Matrix Metalloproteinase Activity in Chondrocytes Isolated from Bovine and Porcine Articular Cartilage

Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2

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