Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gene expression of matrix metalloproteinase 3 (MMP-3 = stromelysin) was examined in the skin fibroblasts obtained from patients with severe recessive dystrophic epidermolysis bullosa (RDEB). Steady-state mRNA level of MMP-3 was selectively increased in the unstimulated RDEB cells by a post-transcriptional mechanism. A parallel study on the susceptibility of type VII collagen to MMPs revealed that this type of collagen is degraded by MMP-3, but not by MMP-1 (collagenase). These data suggest that MMP-3 may play an important role in the blister formation fo the skin in RDEB patients by the degradation of anchoring fibrils consisting of type VII collagen.
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PMID:Increased gene expression of matrix metalloproteinase-3 (stromelysin) in skin fibroblasts from patients with severe recessive dystrophic epidermolysis bullosa. 170 17

Type VII collagen is a major component of anchoring fibrils, which are 800-nm-long centrosymmetrically cross-banded fibrils that are believed to secure the attachment of certain epithelial basement membranes to the underlying stromal matrix. The ultrastructure of the anchoring fibrils is highly variable, suggesting that the fibrils are flexible. Flexibility measurements along the length of the triple-helical domain of type VII procollagen indicate that major flexible sites correlate well with known discontinuities in the (Gly-X-Y)n repeating sequence. Therefore, the helical disruptions may account for the tortuous shapes of anchoring fibrils observed ultrastructurally. The centrosymmetrical banding pattern observed for anchoring fibrils results from the unstaggered lateral packing of antiparallel type VII collagen dimers that form these structures. This antiparallel arrangement is specified by disulfide bonds formed at the margins of a 60-nm overlap of the amino termini. As long as these disulfide bonds remain intact, they protect the amino-terminal overlapping triple helices from collagenase digestion. This disulfide-bonded pair of triple helices is termed C-1. Large nonhelical domains (NC-1) extend from both ends of the anchoring fibrils and are believed to interact with the basement membrane or with anchoring plaques. Rotary shadowing of the NC-1 domains showed trident-like shapes, suggesting that a single alpha-chain contributed the structure of each arm and that the three arms were extended. Biochemical and biophysical analyses of NC-1 domains independently confirm these suggestions and imply that the arms of NC-1 domains are identical and individually capable of interactions with basement membrane components, potentially allowing trivalent interaction of type VII collagen with various macromolecules.
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PMID:The relationship of the biophysical and biochemical characteristics of type VII collagen to the function of anchoring fibrils. 211 41

Type VII procollagen has been characterized as a product of epithelial cell lines. As secreted, it contains a large triple-helical domain terminated by a multi-globular-domained carboxyl terminus (NC-1), and a smaller amino-terminal globule (NC-2). The triple helix and the NC-1 domain have previously been identified in anchoring fibril-containing tissues by biochemical and immunochemical means, leading to the conclusion that type VII collagen is a major component of anchoring fibrils. In order to better characterize the tissue form of type VII collagen, we have produced a panel of monoclonal antibodies which recognize the NC-1 domain. Peptide mapping of these epitopes indicate that they are independent and span approximately 125,000 kDa of the total 150,000 kDa of each alpha chain contained in NC-1. All these antibodies elicit immunofluorescent staining of the basement membrane zone in tissues. Type VII collagen has been extracted from tissues. As previously reported, it is smaller than type VII procollagen, (Woodley, D. T., Burgeson, R. E., Lunstrum, G. P., Bruckner-Tuderman, L., and Briggaman, R. A., submitted for publication), and we now find that it predominantly occurs as a dimer. Following clostridial collagenase digestion, intact NC-1 has been recognized, indicating that the difference in apparent Mr between the tissue form of the molecule and type VII procollagen results from modification of the amino terminus. The size of the amino-terminal globule has been determined to be between approximately 96 and 102 kDa. Rotary shadowing analyses of extracted molecules indicate that dimeric molecules contain the NC-1 domain, but are missing intact NC-2. We propose that the tissue form monomer, Mr = 960,000, be referred to as "type VII collagen." These studies strongly suggest that anchoring fibrils contain dimeric molecules with intact NC-1 domains. The data also support the previous suggestion that the NC-2 domain is involved in the formation of disulfide bond-stabilized type VII collagen dimers, and is subsequently removed by physiological proteolytic processing.
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PMID:Anchoring fibrils contain the carboxyl-terminal globular domain of type VII procollagen, but lack the amino-terminal globular domain. 244 95

Type VII collagen is the major structural protein of anchoring fibrils, which are believed to be critical for epidermal-dermal adhesion in the basement membrane zone of the skin. To elucidate possible mechanisms for the turnover of this protein, we examined the capacities of two proteases, human skin collagenase, which degrades interstitial collagens, and a protease with gelatinolytic and type IV collagenase activities, to cleave type VII collagen. At temperatures below the denaturation temperature, pepsin cleaves type VII collagen into products of approximately 95 and approximately 75 kDa. Human skin collagenase cleaved type VII collagen into two stable fragments of approximately 83 and approximately 80 kDa, and the type IV collagenase (gelatinase) produced a broad band of approximately 80 kDa as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Cleavage of type VII collagen was linear with time and enzyme concentration for both enzymes. Although the Km values were similar for both enzymes, the catalytic rate of cleavage by type IV collagenase is much faster than by interstitial collagenase, and shows a greater rate of increase with increasing temperature. Sequence analysis of the cleavage products from both enzymes showed typical collagenous sequences, indicating a relaxation in the helical part of the type VII collagen molecule at physiological temperature which makes it susceptible to gelatinolytic degradation. Interstitial collagenase from both normal skin cells and cells from patients with recessive dystrophic epidermolysis bullosa, a severe hereditary blistering disease in which both an anchoring fibril defect and excessive production of collagenase can be observed, produced identical cleavage products from type VII collagen. These data suggest a pathophysiological link between increased enzyme levels and the observed decrease or absence of anchoring fibrils.
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PMID:Cleavage of type VII collagen by interstitial collagenase and type IV collagenase (gelatinase) derived from human skin. 253 92

In July 1986, a 46-year old male patient was admitted for a bullous skin disease of 4 years' duration. The disease fulfilled all the criteria of epidermolysis bullosa acquisita (EBA), as laid down by Roenigk and Pearson. Despite a guided investigation, none of the diseases classically associated with EBA could be found, but it must be noted that immunological stigmata of an old hepatitis B were present. After failures or partial results with prednisone alone (1 mg/kg/day from August to October 1986), then methotrexate (30 mg/week) combined with prednisone (20 mg/day), the patient was treated with colchicine in doses of 2 mg per day, and within a fortnight a dramatic improvement of buccal mucosal lesions and cutaneous fragility was observed. Colchicine was withdrawn, but 5 days later bullae and erosions of the mucosa reappeared. The reintroduction of colchicine in the same doses (2 mg/day) resulted in remission of the lesions. The disease has now remained stable for one year under colchicine 1 mg/day. Four attempts at reducing this dosage to 1 mg every other day brought about the recurrence of a few bullae and of cutaneous fragility. To our knowledge, colchicine has not yet been reported to be effective in the treatment of EBA. Its effectiveness may be due, to a great extent, to its immunomodulating properties, notably on some functions of neutrophils the role of which in the pathogenesis of bullous lesions seems to have been established. By modulating collagen synthesis and collagenase activity colchicine might induce structural modifications of the EBA antigen, identified as the carboxyterminal group of type VII collagen, and inhibit its recognition by autoantibodies.
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PMID:[Value of colchicine in treating acquired epidermolysis bullosa]. 267 32

H-ras-transformed human bronchial epithelial cells (TBE-1) secrete a single major extracellular matrix metalloprotease which is not found in the normal parental cells. The enzyme is secreted in a latent form of 72 kDa, which can be activated to catalyze the cleavage of the basement membrane macromolecule type IV collagen. The substrates in their order of preference are: gelatin, type IV collagen, type V collagen, fibronectin, and type VII collagen; but the enzyme does not cleave the interstitial collagens or laminin. This protease is identical to gelatinase isolated from normal human skin explants, normal human skin fibroblasts, and SV40-transformed human lung fibroblasts. Based on its ability to initiate the degradation of type IV collagen in a pepsin-resistant portion of the molecule, it will be referred to as type IV collagenase. This enzyme is most likely the human analog of type IV collagenase detected in several rodent tumors, which has the same molecular mass and has been linked to their metastatic potential. Type IV collagenase consists of three domains. Two of them, the amino-terminal domain and the carboxyl-terminal domain, are homologous to interstitial collagenase and human and rat stromelysin. The middle domain, of 175 residues, is organized into three 58-residue head-to-tail repeats which are homologous to the type II motif of the collagen-binding domain of fibronectin. Type IV collagenase represents the third member of a newly recognized gene family coding for secreted extracellular matrix metalloproteases, which includes interstitial fibroblast collagenase and stromelysin.
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PMID:H-ras oncogene-transformed human bronchial epithelial cells (TBE-1) secrete a single metalloprotease capable of degrading basement membrane collagen. 283 83

Anchoring fibrils are specialized fibrous structures found in the subbasal lamina underlying epithelia of several external tissues. Based upon their sensitivity to collagenase and the similarity in banding pattern to artificially created segment-long spacing crystallites (SLS) of collagens, several authors have suggested that anchoring fibrils are lateral aggregates of collagenous macromolecules. We recently reported the similarity in length and banding pattern of anchoring fibrils to type VII collagen SLS crystallites. We now report the construction and characterization of a murine monoclonal antibody specific for type VII collagen. The epitope identified by this antibody has been mapped to the carboxyl terminus of the major helical domain of this molecule. The presence of type VII collagen as detected by indirect immunofluorescence in a variety of tissues corresponds exactly with ultrastructural observations of anchoring fibrils. Ultrastructural immunolocalization of type VII collagen using a 5-nm colloidal gold-conjugated second antibody demonstrates metal deposition upon anchoring fibrils at both ends of these structures, as predicted by the location of the epitope on type VII collagen. Type VII collagen is synthesized by primary cultures of amniotic epithelial cells. It is also produced by KB cells (an epidermoid carcinoma cell line) and WISH (a transformed amniotic cell line).
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PMID:Type VII collagen is a major structural component of anchoring fibrils. 377 48

Enzymes and chemicals were used to analyse the biochemical structure of the antigenic epitope recognized by GDA-J/F3 monoclonal antibody (MoAb) in the human sperm tail fibrous sheath. Treatment of sperm dried onto slides with trypsin or dispase enzymes abolished their immunofluorescence staining with GDA-J/F3 MoAb, thus indicating the proteinaceous nature of the antigen. The proteolytic cleavage of GDA-J/F3 protein by trypsin, which also caused sperm decapitation, indicated the presence of peptide bonds involving the carboxyl groups of the basic amino acids, arginine and/or lysine. The epitope was also glycosylated as demonstrated by its sensitivity to sodium metaperiodate treatment which was dose-dependent. The GDA-J/F3 antigenic epitope lacked sialic acid since pre-treatment of spermatozoa with sialidase enzyme (neuraminidase) had no effect on their reactivity with the antibody. The lack of collagenous domains in the GDA-J/F3 antigen was demonstrated by the failure of collagenase to abrogate sperm immunostaining with the MoAb. Furthermore, type VII collagen of the skin basement membrane (BM) was previously thought of as a potential target antigen for GDA-J/F3 MoAb. This was ruled out since several monoclonal and polyclonal antibodies failed to detect the antigen in the spermatozoa using immunofluorescence and Western blotting. These data, therefore, show that the target antigen for GDA-J/F3 MoAb is a non-collagenous asialo-glycoprotein, and by inference provide the first evidence for the glycosylation of the sheath proteins as another step of post-translational modification occurring during sperm tail development.
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PMID:The target antigen for GDA-J/F3 monoclonal antibody in the human sperm tail fibrous sheath is a non-collagenous asialo-glycoprotein: implications and significance. 752 22

Collagenase and stromelysin expression in recessive dystrophic epidermolysis bullosa (RDEB) was studied at both the protein and the gene expression levels in fibroblast cultures. The amount of enzyme protein in the culture medium, as determined using a specific enzyme assay, showed a 9.7-fold increase in collagenase and a 2.7-fold increase in stromelysin in RDEB fibroblasts (n = 4 patients) compared with controls (n = 3 subjects with normal skin). Collagenase activity was extremely high in all RDEB fibroblasts. Gene expression, as assessed by Northern blot hybridization, was increased in two sets of RDEB fibroblasts with respect to collagenase, and in two other sets of RDEB fibroblasts with respect to stromelysin. The effect of interleukin-1 alpha (IL-1 alpha) on metalloproteinase expression was also examined. The results revealed that: 1) collagenase and stromelysin expression was variably increased at both the protein and the gene expression levels in RDEB fibroblasts; (2) the gene expression level did not always reflect the corresponding protein level; and (3) IL-1 alpha produced a differential effect on collagenase and stromelysin expression. Although the causative gene for RDEB is a type VII collagen, the abnormal expression of collagenase and/or stromelysin is still important in considering the pathophysiology of RDEB.
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PMID:Expression of collagenase and stromelysin in skin fibroblasts from recessive dystrophic epidermolysis bullosa. 762 51

Epidermolysis bullosa acquisita (EBA) is an acquired blistering skin disease characterized by the presence of IgG autoantibodies that recognize type VII (anchoring fibril) collagen. In this study, we have mapped the antigenic epitopes within the type VII collagen alpha chain by Western immunoblotting analysis with sera from 19 patients with EBA, using bacterial collagenase- or pepsin-resistant portions of type VII collagen and a panel of 12 recombinant fusion proteins corresponding to approximately 80% of the primary sequence of the alpha 1 (VII) collagen polypeptide. These studies identified four major immunodominant epitopes localized within the amino-terminal, noncollagenous (NC-1) domain. In addition to EBA, sera from three patients with bullous systemic lupus erythematosus (BSLE) were tested. The pattern of epitopes recognized by these sera were similar to those noted with EBA, suggesting that the same epitopes could serve as autoantigens in both blistering conditions. In contrast, sera from healthy controls or from patients with unrelated blistering skin diseases did not react with type VII collagen epitopes. Collectively, the results indicate that the immunodominant epitopes in EBA and BSLE lie within the noncollagenous regions of type VII collagen. The precise role of the circulating autoantibodies in the pathogenesis of these blistering diseases remains to be elucidated. Conceivably, however, such antibodies could disrupt the assembly of type VII collagen into anchoring fibrils and/or interfere with their interactions with other extracellular matrix molecules within the cutaneous basement membrane zone.
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PMID:Epitope mapping of type VII collagen. Identification of discrete peptide sequences recognized by sera from patients with acquired epidermolysis bullosa. 769 88


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