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:3.4.23.5 (cathepsin D)
4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibronectin is one of the major adhesive glycoproteins and bears interaction sites for both cell receptors and the extracellular matrix. Disappearance of fibronectin is the first step of cellular transformation in carcinogenesis. This phenomenon has been ascribed to increased proteolysis of fibronectin or of its cellular receptor. Results obtained during previous studies by the authors have shown that the fibronectin molecule has latent proteolytic activities which become apparent only after the action of other external proteases. Two proteinases, FN-gelatinase and FN-laminase, were identified in cathepsin D fibronectin digest. The acute activity of these two proteases is responsible for degradation of the extracellular matrix. Furthermore, the sequences and functions of both enzymes share a number of features with retroviral proteases.
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PMID:[Proteolytic potential of fibronectin and degradation of extracellular matrix]. 229 Jul

The purified 190-kDa fibronectin fragment produced by cathepsin D can be spontaneously activated in the presence of CaCl2. This activation generates new proteolytic activities and also results in the formation of several subfragments. One of them exhibits the activity of FN-gelatinase that preferentially splits type I denatured collagen and fibronectin (see preceding paper). In this work we describe the purification and characterization of another fragment (25 kDa), issued from the same autodigest. This fragment may be activated to yield another proteinase, that splits preferentially laminin and denatured collagen type I. This enzyme will be referred as FN-laminase. Purified FN-laminase specifically reacted with antibodies against fibronectin. The specificity of bond cleavage by FN-laminase was studied with various synthetic peptides analogous to collagen repeats. FN-laminase cleaves the Ala-Gly bond in the sequence GPAGPR; the arginine residue in position P3' is important for this cleavage. The enzyme is inhibited by pepstatin A and phenylmethanesulfonyl fluoride, like retroviral aspartic proteinases. It is also inhibited by EDTA. No inhibition was obtained with 1,10-phenanthroline or 4-chloromercuribenzoate, inhibitors of Zn-metalloproteinases or cysteine proteinases, respectively.
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PMID:Potential proteolytic activity of fibronectin: fibronectin laminase and its substrate specificity. 233 18

The domain structure of human plasma fibronectin was investigated by using heparin-binding and antibody reactivity of fibronectin and its proteolytically derived fragments. Digestion of human plasma fibronectin with a combination of trypsin and cathepsin D produced six major fragments. Affinity chromatography showed that one fragment (Mr 45 000) binds to gelatin and three fragments (Mr 31 000, 36 000, and 61 000) bind to heparin. The 31K fragment corresponds to NH2-terminal fragments isolated from other species. The 36K and 61K fragments are derived from a region near the C-terminus of the molecule and appear to be structurally related as demonstrated by two-dimensional peptide maps. A protease-sensitive fragment (Mr 137 000), which binds neither gelatin nor heparin but which has been shown previously to be chemotactic for cells [Postlethwaite, A. E., Keski-Oja, J., Balian, G., & Kang, A. H. (1981) J. Exp. Med. 153, 494-499], separates the NH2-terminal heparin- and gelatin-binding fragments from the C-terminal 36K and 61K heparin-binding fragments. A monoclonal antibody to fibronectin that recognized the 61K heparin-binding fragment was used to isolate a sixth fragment (Mr 34 000) that did not bind to heparin or gelatin and that represents a difference between the 61K and 36K heparin-binding fragments. Cathepsin D digestion produced an 83K heparin-binding, monoclonal antibody reactive fragment that contains the interchain disulfide bond(s) linking the two fibronectin chains at their C-termini. The data indicate that plasma fibronectin is a heterodimeric molecule consisting of two very similar but not identical chains (A and B). In contrast, enzymatic digestion of cellular fibronectin produced a 50K heparin-binding fragment lacking monoclonal antibody reactivity which suggests that the cellular fibronectin subunit is similar to the plasma A chain in enzyme susceptibility but contains a larger heparin-binding domain. A model relating the differences in the three fibronectin polypeptides to differences in published cDNA sequences is presented.
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PMID:Domain structure of human plasma and cellular fibronectin. Use of a monoclonal antibody and heparin affinity to identify three different subunit chains. 241 23

The determinant specificities of five monoclonal anti-fibronectin antibodies, designated BC7, CE9, BD4, AB3 and CPG1, were defined and mapped within intact human plasma fibronectin by immunoblot analyses with defined fragments of fibronectin. The latter were derived by tryptic, chymotryptic or cathepsin D digestion of the intact molecule and fractionated by DE-cellulose chromatography and gelatin and/or heparin affinity chromatography. Monoclonal BC7 recognizes intrachain disulphide-formed determinants within the 27,000 MW N-terminal domain; monoclonal CE9 recognizes determinants within an 18,000 MW fragment immediately adjacent to the carboxyl end of the gelatin-binding domain; monoclonal BD4 recognizes determinants within the cell-adhesive domain and within 150,000 of the N-terminus; monoclonal AB3 recognizes intrachain disulphide-formed determinants within 35,000 of the COOH-terminus of the intact molecule and detectable only on the alpha-chain polypeptide subunit; and monoclonal CPG1 recognizes determinants present on both chains of the intact molecule and immediately adjacent to the interchain disulphide bonds at the COOH-terminus. None of the epitopes recognized by these monoclonal antibodies is present at alternative regions of the intact molecule. Fab fragments of each of these monoclonal antibodies were incubated with gelatin-coated sheep erythrocytes which had been reacted with a fixed amount of intact plasma fibronectin. When these target particles were incubated with monolayers of human monocytes and the resultant rosettes were quantitated, the Fab fragments of BD4 markedly inhibited the proportion of monocytes binding these fibronectin-bearing targets, whereas none of the other Fab fragments had an inhibitory effect. Thus, monocyte fibronectin receptors which mediate adherence of fibronectin bridges to a target via gelatin recognize regions within the cell-adhesive domains of intact fibronectin but not regions at the amino or carboxy terminals.
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PMID:Identification with monoclonal antibodies of different regions of human plasma fibronectin, including that which interacts with human monocyte fibronectin receptors. 257 23

An examination of the DNA binding domain structure of bovine plasma fibronectin (Fn) was undertaken by a combination of limited proteolytic cleavage and Western blotting. A time course digestion of fibronectin with cathepsin D produced a number of proteolytic fragments possessing DNA binding activity. After two min digestion, two DNA binding fibronectin fragments of Mr approximately 180kd and 120kd were detected. Upon further digestion, a fibronectin fragment of Mr 18kd was detected. Thus it would appear that under physiological ionic strength only a single DNA binding domain exists in the fibronectin molecule. It was also demonstrated that the interaction of fibronectin with DNA is not ionic in nature, as heat denaturation of protein totally abolishes the DNA binding activity. An examination of possible sequence specificity of DNA binding activity of fibronectin was also undertaken by dot blotting the bovine plasma fibronectin and using [32P] labelled lambda FC 40 DNA containing approximately 16 kd of 5' end of the chicken fibronectin gene. Its binding to fibronectin was approximately twice the binding of [32P] labelled wild type lambda, where as binding to control of equimolar concentration of calf thymus histone H 2 A was approximately equal. The use of a smaller subcloned region, a approximately 1.9kb fragment of DNA from the 5' end of chicken fibronectin gene and wild type lambda DNA showed approximately 2 fold increase in histone binding and approximately 7 fold increase in fibronectin binding, indicating preferential fibronectin binding with eukaryotic DNA as compared to prokaryotic DNA. Further investigation of sequence specificity showed that a 0.45kb DNA fragment from the 5' end of chicken fibronectin gene, containing a number of elements characteristic of promoter, demonstrated approximately 2 fold higher level of binding with fibronectin and approximately 3.5 fold less binding activity with equimolar concentration of histone H2A when compared with a 1.4kb fragment of chicken fibronectin gene from the 1st exon. These results suggest fibronectin binding may be preferential to the promoter region of its own gene which could have possibly a regulatory function.
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PMID:The interaction between fibronectin and DNA. 275 Dec 62

Eight liver biopsy specimens from five patients with PAS-negative intracisternal hyalin were investigated by immunofluorescence for: (1) immunoglobulins (Ig) G, A, M, D, E; (2) light chains (kappa and lambda); (3) complement components C1q, C4, C3c, C5, C9; (4) C1-inactivator; (5) C3-activator; (6) alpha 1-antitrypsin; (7) alpha 1-antichymotrypsin; (8) plasminogen; (9) fibrinogen; (10) fibrinogen breakdown products D and E; (11) fibronectin; (12) prealbumin; (13) albumin; (14) betalipoprotein; (15) apolipoprotein; (16) alpha 1- and alpha 2-glycoprotein; (17) cholinesterase; (18) ceruloplasmin; (19) haemopexin; (20) myoglobin; (21) placenta lactogen; (22) transferrin; (23) actin; (24) myosin; (25) cathepsin D; and (26) hepatitis B surface and core antigens (HBsAg and HBcAg). The globules reacted significantly with antisera against C3c (three patients), C4 (three patients), C3-activator (one patient) and fibrinogen (two patients). The cause of the protein accumulation is not clear. Serial studies indicate the possibility of a disturbance of protein secretion and an as yet unidentified immune complex disorder.
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PMID:Immunohistological investigations of PAS-negative globular intracisternal hyalin in human liver biopsy specimens. 285 88

The plasma levels of the opsonic glycoprotein fibronectin are decreased in patients with fulminant hepatic failure, which may be an important factor in their impaired host-defense. Twenty-nine patients in fulminant hepatic failure were studied on admission, and the mean fibronectin level in Grade 0-2 encephalopathy was 82 micrograms per ml (range = 0 to 150) and in Grade 3-4 encephalopathy 61 micrograms per ml (range = 5 to 158) as compared to normal controls (268 micrograms per ml, range = 178 to 380, n = 62). No fibronectin degradation products could be detected in fulminant hepatic failure plasma by sodium dodecyl sulfate-gel electrophoresis on a polyacrylamide gradient (5 to 15%) followed by immunoblotting onto nitrocellulose with detection using a rabbit antihuman fibronectin antiserum visualized with a peroxidase conjugate. The plasma levels of the marker proteolytic enzyme cathepsin D were significantly elevated in fulminant hepatic failure (120 +/- 31 mU per ml per hr) as compared to the normal controls (18 +/- 2.1 mU per ml per hr, n = 10, p less than 0.01). Cross-immunoelectrophoresis of fulminant hepatic failure plasma for fibronectin on agarose plates gave an additional slower migrating peak in 15 of the 29 patients, as well as that of fibronectin, which corresponded to the fibronectin complex reported by other workers in leukemia. An intermediate gel containing antihuman fibrinogen demonstrated fibrinogen to be one component of this complex. Binding of other substances to fibronectin will reduce its apparent biological activity and may be the result of their lack of clearance by the damaged liver.
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PMID:Characterization of the molecular forms of fibronectin in fulminant hepatic failure. 309 66

Oleic acid binds in a saturable fashion to human plasma fibronectin (FN). Analysis of the binding indicated the presence of a high affinity binding site with nKa approximately equal to 10 uM-1. Furthermore, it was found that binding of sodium oleate to FN modulated its susceptibility to degradation by various proteinases. FN saturated with sodium oleate was hydrolysed at a higher rate by trypsin, cathepsin D, thermolysin and pancreatic elastase than native FN. In contrast, sodium oleate inhibits the activity of two human granulocyte proteinases, human leucocyte elastase (HLE) and cathepsin G on either FN or on their respective specific synthetic substrates (at concentrations ranging from 10(-6) mM to 10 mM). Cathepsin G inhibition was non-competitive and gave a Ki in the 10 uM range similar to the previously reported inhibitory constant of oleic acid toward HLE.
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PMID:Effect of sodium oleate on the hydrolysis of human plasma fibronectin by proteinases. 329 75

Evidence is presented that fibronectin (FN) polypeptide chain contains a latent proteinase. Human plasma FN was cleaved with cathepsin D into three main fragments: 140-kDa and 70-kDa single-chain and 140-kDa double-chain polypeptides. Their separation was achieved according to their affinity for heparin-Sepharose. A single-chain 140-kDa fragment (H-1) was eluted in the first peak. This peptide corresponds to the already described fragment that originates from the central part of FN; it contains a low-affinity heparin-binding site, one free SH group, and a cell-binding site. After reduction and further purification by preparative polyacrylamide gel electrophoresis, this fragment revealed a spontaneous decomposition, which could be attributed to proteolytic degradation. The subfragments, ranging from 25 to 95 kDa, yielded the same proteolytically active doublet of 28-30 kDa when tested by NaDodSO4/polyacrylamide gel electrophoresis in a gel containing copolymerized gelatin or fibrinogen. The proteolytic activity was inhibited by specific SH proteinase inhibitors. The proteinase forms a labeled complex after its incubation with 125I-labeled cystatin. Neither FN, cathepsin D, nor any products from previous purification steps were proteolytically active under the conditions of the assay. It was suggested that the same fragment may also yield an inhibitor, since structural analogies were found between the cell-binding region of FN and SH proteinase inhibitors.
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PMID:Potential proteolytic activity of human plasma fibronectin. 352 28

Fibronectin was partially digested using the lysosomal proteinase cathepsin D and the fragments produced tested for their effect on the rate of DNA synthesis in quiescent Chinese Hamster Fibroblasts (CH23). A mitogenically active digest was produced after digestion of fibronectin with cathepsin D for 2 to 3h at a 1:200 (w/w) ratio of enzyme to substrate at 37 degrees C. Affinity chromatography of the active digest on both gelatin and heparin 4BCl columns demonstrated that the active fragment was gelatin-nonbinding but heparin-binding, and therefore derived from one of the two or three heparin binding domains of intact fibronectin. The active fragment was found to have a Mr35,000 by gel filtration on sephacryl S200. A dose-response curve of the mitogenic fragment purified by gel filtration against DNA synthesis showed it to be maximally active at a concentration of approximately 10 micrograms/ml.
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PMID:The mitogenic activity of a heparin-binding fibronectin fragment (Mr 35,000) produced by cathepsin D digestion. 370 69


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