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PubMed1998

The metallo-disintegrin ADAM10 (MADM) from bovine kidney has type IV collagenase activity in vitro.

The metallo-disintegrins (ADAMs) are a family of mammalian proteins with significant amino acid sequence identity and a domain organisation similar to the snake venom metalloproteinases (reprolysins). They have been implicated in a wide variety of processes such as cell-cell and cell matrix adhesion and proteolysis of the extracellular matrix in a wide variety of cell types. They may also be involved in events such as the processing of plasma membrane proteins, proteolysis in the secretory pathway and pro-cytokine conversion processes. Due to the close relationship of the ADAM proteins with snake venom enzymes which have been demonstrated to be type IV collagenases, we investigated whether purified bovine ADAM10 could cleave basement membrane type IV collagen. We show here that ADAM10 purified from bovine kidney can cleave a basement membrane collagen type IV preparation as assessed by SDS-PAGE analysis and novel epitope recognition with a specific antibody to type IV collagen. The demonstration that a metallo-disintegrin displays a type IV collagenase activity may be relevant to tumour metastasis and may have general relevance to extracellular re-modeling in renal pathology and a variety of other pathological states where compromise of the basement membrane is involved.

ADAM Proteins↗
PubMed2000

EC3, a heterodimeric disintegrin from Echis carinatus, inhibits human and murine alpha4 integrin and attenuates lymphocyte infiltration of Langerhans islets in pancreas and salivary glands in nonobese diabetic mice.

The venom of Echis carinatus suchoreki contains a monomeric disintegrin echistatin (Mr 5,500 Da) that strongly inhibits alphaIIbbeta3, alphavbeta3, and alpha5beta1 integrins and a heterodimeric disintegrin called EC3 (M(r) 14,762 Da). At nanomolar concentration, EC3 inhibits adhesion of human cell lines expressing alpha4beta1 and alpha4beta7 to immobilized VCAM-1; it has a lower inhibitory effect on alpha5beta1-mediated cell adhesion. In this study, we demonstrated that EC3, in contrast to echistatin, inhibited binding of monoclonal anti-alpha4 and anti-alpha5 antibodies to cells expressing alpha4beta7. In a dose-dependent manner and to the same extent, EC3 inhibited adhesion of Jurkat cells and murine splenic lymphocytes to immobilized VCAM-1, whereas echistatin was not active. EC3 injected intraperitoneally into nonobese diabetic (NOD mice) suppressed development of insulitis and sialoadenitis, whereas echistatin had no significant effect. We propose that the effect of EC3 is mediated, at least, in part, by blocking alpha4beta1 and alpha4beta7 on murine lymphocytes.

Amino Acid Sequence↗
PubMed2000

Edema induction by the disintegrin-like/cysteine-rich domains from a Bothrops atrox hemorrhagin.

Viperine and crotaline snake venoms contain one or more hemorrhagic metalloproteases called hemorrhagins. The most potent hemorrhagins belong to the P-III class and have, in addition to the protease domain, disintegrin-like and cysteine-rich domains. Although proteolytic degradation of vascular endothelium basement membrane has been established to be the main factor responsible for hemorrhage, several studies reveal other factors that actually do facilitate this process. Recent evidence has shown that the nonprotease domains of the P-III class hemorrhagins are able to inhibit the platelet aggregation by blocking essential procoagulant integrins on platelets. In this study we report the identification of a hemorrhagin from Bothrops atrox venom. This enzyme, a P-III class metalloprotease, undergoes an apparent spontaneous degradation, releasing a proteic fragment containing the disintegrin-like/cysteine-rich domains. This fragment shows the capability to induce an edematogenic process, suggesting the existence of a still unknown nonenzymatic mechanism of vascular permeability increase.

Amino Acid Sequence↗
PubMed2001

Expression and enzymatic activity of human disintegrin and metalloproteinase ADAM19/meltrin beta.

The adamalysins are involved in proteolysis, adhesion, fusion, and intracellular signaling. Human ADAM19/adamalysin-19 (A disintegrin and metalloproteinase 19) was identified from primary dendritic cell cDNA libraries. It has a signal sequence, a pro-domain with a "cysteine-switch" residue, a metalloproteinase domain with a zinc-binding site, a disintegrin, a cysteine-rich domain, an epidermal-growth-factor-like domain, a transmembrane domain, and a cytoplasmic domain with putative SH3 ligand binding sites. Its mRNA was expressed in the placenta, heart, bladder, lymph nodes, and leukocytes, colorectal adenocarcinoma SW 480, and other organs/cells. The hADAM19 recombinant protein was expressed in human cells. It formed a complex with and cleaved alpha-2 macroglobulin (alpha2-M). Its proteolytic activity was blocked by 1,10-phenanthroline, EDTA, EGTA, and a synthetic matrix metalloproteinase (MMP) inhibitor and not by the tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2. It did not cleave the MMP substrates tested, e.g., type I collagen and gelatin, casein, and four peptide substrates. Thus, hADAM19 is an active metalloproteinase and may have a specific substrate profile.

ADAM Proteins↗
PubMed1998

Voltage-dependent activation of frog eggs by a sperm surface disintegrin peptide.

Fertilin, a sperm protein of the metalloprotease/disintegrin/cysteine-rich (MDC) family, plays a critical role in sperm-egg binding in mammals. Peptides corresponding to the disintegrin domain of fertilin and antibodies against fertilin have been shown to inhibit mammalian sperm-egg binding and fusion. A protein from the same family, xMDC16, was recently cloned from frog (Xenopus laevis) testis and was found to be involved in frog sperm-egg binding. Here we report that xMDC16 is localized predominantly on the posterior surface of egg jelly-activated sperm, and peptides from the disintegrin domain of this protein activate eggs when applied near the egg surface. Egg activation was dependent on (1) specific amino acid residues (KTX); (2) the presence of divalent cations, but not external Ca2+ alone; and (3) voltage across the egg plasma membrane. This is the first demonstration of egg activation in vertebrates by the surface application of a peptide derived from a sperm surface protein, supporting a model for egg activation that involves a signal transducing receptor for sperm in the egg's plasma membrane.

Animals↗
PubMed1998

Neural crest-specific and general expression of distinct metalloprotease-disintegrins in early Xenopus laevis development.

Metalloprotease-disintegrins are a family of membrane-anchored glycoproteins that have been implicated in diverse cellular processes, including fertilization and myoblast fusion, release of TNFalpha from the plasma membrane, and neurogenesis. Here we report the cloning of cDNAs encoding three full-length (xMDC9, xMDC11b, and xMDC13), and one partial (xMDC11a) metalloprotease-disintegrin from the amphibian Xenopus laevis, and the analysis of their expression during early X. laevis development and in adult tissues. The most notable finding was the highly localized and specific expression pattern of xmdc11a at the tailbud stage in the cranial neural crest and in a subset of neural tube cells in the trunk region. In contrast, expression of the closely related xmdc11b was not detectable during the early stages of X. laevis development, and remained low in the adult tissues examined here. Distinct expression patterns were also observed for two other highly related X. laevis genes, xmdc13 and adam13 (Alfandari et al., 1997). While adam13 is expressed in the somitic mesoderm and in neural crest cells, but not in adult testis, xmdc13 expression is low and ubiquitous in the developing embryo, but is clearly present in adult testis. Finally, xmdc9, the putative orthologue of human and mouse mdc9, was found at all stages of development, and in all tissues examined, suggesting a function that may be utilized by most or all cells. The noteworthy features of these four xmdc genes and the implications of their distinct spatial and temporal expression patterns are discussed.

Amino Acid Sequence↗
PubMed2004

Comparative proteomics and subtyping of venom phospholipases A2 and disintegrins of Protobothrops pit vipers.

To explore the venom diversity and systematics of pit vipers under the genus Protobothrops, the venom phospholipases A2 (PLA2s) of P. mangshanensis, P. elegans and P. tokarensis were purified and characterized for the first time. The results were compared with the corresponding venom data of other co-generic species including P. mucrosquamatus, P. flavoviridis and P. jerdonii. Based on sequence features at the N-terminal regions, we identified five PLA2 subtypes, i.e., the Asp49-PLA2s with N6, E6 or R6 substitution and the Lys49-PLA2. However, not all subtypes were expressed in each of the species. Venom N6-PLA2s from P. mangshanensis and P. tokarensis venom were weakly neurotoxic toward chick biventer cervicis tissue preparations. The venoms of P. tokarensis and P. flavoviridis contained identical PLA2 isoforms. In most Protobothrop disintegrins, sequences flanking the RGD-motif are conserved. Phylogenetic analyses based on amino acid sequences of both families of the acidic PLA2s and the disintegrins clarify that these species could belong to a monophyletic group.

Amino Acid Sequence↗
PubMed2005

Inhibition of adipogenesis by RGD-dependent disintegrin.

Adipogenesis plays a central role in obesity development. The processes of adipogenesis include migration, adhesion, proliferation and survival of preadipocytes and differentiation to mature adipocytes. Many of these biological functions are related to integrins. Here, we found that snake venom-derived arginine-glycine-aspartic acid (RGD)-containing disintegrin inhibited adipogenesis. Rhodostomin but not rhodostomin RGD mutants (RGE-Rn and AKGDWN-Rn) caused the detachment of primary cultured preadipocyte. Furthermore, rhodostomin also inhibited focal adhesion of preadipocyte, including the inhibition of the expression of focal adhesion kinase (FAK) and FAK phosphorylation, assembly of vinculin and reorganization of actin cytoskeleton. Cell viability of preadipocytes was decreased after rhodostomin treatment in a concentration-dependent manner. The results of flow cytometric analysis showed that rhodostomin induced cell apoptosis. In addition, chromatin condensation was observed in DAPI staining. The increase of Bax expression and activation of capsase-3 was detected following rhodostomin treatment. Addition of dexamethasone, IBMX and insulin induced differentiation of preadipocytes into mature adipocytes and treatment of cells with rhodostomin during the initial 3 days showed less mature adipocytes following 9-10 days of differentiating period. The triglyceride content and gene expression of peroxisome proliferators-activated receptor gamma (PPARgamma) and leptin also decreased in response to the treatment of rhodostomin. These results suggest that disintegrin inhibits processes of adipogenesis and may be developed to treat obesity.

Actins↗
PubMed2006

Snake venom metalloproteases--structure and function of catalytic and disintegrin domains.

Snake venoms are relevant sources of toxins that have evolved towards the engineering of highly active compounds. In the last years, research efforts have produced great advance in their understanding and uses. Metalloproteases with disintegrin domains are among the most abundant toxins in many Viperidae snake venoms. This review will focus on the structure, function and possible applications of the metalloprotease and disintegrin domains.

Amino Acid Sequence↗
PubMed2002

Characterization of a monomeric disintegrin, ocellatusin, present in the venom of the Nigerian carpet viper, Echis ocellatus.

Ocellatusin is a new RGD-containing short monomeric disintegrin. It is a better inhibitor of alpha(5)beta(1) integrin and a more potent inducer of the expression of a ligand-induced binding site epitope on beta(1) integrin subunit than echistatin. In further contrast to echistatin, ocellatusin has a direct chemotactic stimulus on human neutrophils in vitro. The distinct effects of these two close evolutionarily related disintegrins might be explained by the presence of methionine-22 and histidine-29 in the RGD loop of ocellatusin, which are arginine and aspartic acid, respectively, in echistatin. These mutations may modulate the conformation and/or recognition properties of the integrin-binding loop of ocellatusin.

Amino Acid Sequence↗
PubMed2002

Meltrin beta mini, a new ADAM19 isoform lacking metalloprotease and disintegrin domains, induces morphological changes in neuronal cells.

Meltrin beta (ADAM19) is a metalloprotease-disintegrin expressed in the peripheral nervous system and other organs during embryogenesis. We report here an alternatively spliced isoform, meltrin beta mini, that lacks the prodomain, metalloprotease and disintegrin domains. A comparison of the cDNA and genomic sequences suggested the existence of a new exon. This isoform was detected in murine dorsal root ganglion and neuronal cell lines by RT-PCR. Overexpression of meltrin beta mini but not meltrin beta induced neurite outgrowth in neuronal cells. These studies suggest that the novel meltrin beta isoform has a distinct function related to neurogenesis.

ADAM Proteins↗
PubMed1997

Pharmacological activity of the interdomain segment between metalloproteinase and disintegrin domains.

Metalloproteinases (haemorrhagic or non-haemorrhagic), disintegrins and most probably C-type lectin-related proteins are derived by the proteolysis of a common precursor protein. There is a short interdomain segment between the metalloproteinase and disintegrin domains which will be released into the venom. To determine whether this region of the molecule contributes to the biological role of the precursors or the products derived by the proteolysis of the precursors, we synthesized a peptide based on this short segment and examined its toxicity and biological activity. The synthetic peptide did not show any lethal toxicity, anticoagulant and antiplatelet effects. However, the peptide appeared to lower the blood pressure or normotensive rats upon infusion, but did not affect the blood levels of triglyceride, total cholesterol, high-density lipoproteins or low-density lipoproteins. The peptide, however, failed to exhibit any effect on spontaneously hypertensive rats and hence may not have a potential as an antihypertensive agent. Based on these results, we conclude that this interdomain segment may not contribute significantly to the biological activity of precursor proteins.

Animals↗
PubMed1999

Insertion of the Asp-Ser/Phe sequence in the P' position of hirutonin provides molecules having both antithrombin and disintegrin activity.

We have developed novel synthetic peptides that display both antithrombin and disintegrin activity. These peptides were derived from hirutonins, a class of potent proteolytically resistant thrombin inhibitors, in which a dipeptidyl sequence, Asp-Phe or Asp-Ser, was introduced after the proteolytically resistant ketomethylene arginyl glycine isostere. These modified hirutonins inhibited the amidolytic activity of alpha-thrombin (Ki approximately 35 nM), prevented fibrinogen clotting (dTT approximately 100 nM) and inhibited human platelet aggregation and 5-hydroxytryptamine secretion induced by alpha-thrombin (IC50 approximately 600 nM). Unlike their parent hirutonins, they inhibited SFLLR-NH2-induced human platelet aggregation (IC50 approximately 45 microM) without inhibition of 5-HT secretion. These peptides also competed for fibrinogen binding to purified GpIIbIIIa integrin (IC50 approximately microM) and prevented attachment of B16-F10 mouse melanoma cells to vitronectin. We conclude that addition of the dipeptidyl sequence, Asp-Phe or Asp-Ser, in hirutonin molecules confers disintegrin activity. However, this activity was not superior to the activity observed with the linear RGDS peptide and was achieved at the expense of direct antithrombin activity. Additional modifications around the RGD-like adhesion sequence may permit identification of the appropriate conformation for optimal binding to thrombin and to specific integrin receptors.

Animals↗
PubMed2002

Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains.

ADAMTS (A Disintegrin And Metalloproteinase domain, with ThromboSpondin type-1 modules) is a recently described family of zinc-dependent proteases which play important roles in a variety of normal and pathological conditions, including arthritis and cancer. In this work, we report the identification and cloning of cDNAs encoding seven new human ADAMTSs. These novel enzymes have been called ADAMTS-13, -14, -15, -16, -17, -18, and -19. All of them show a domain organization similar to that of previously characterized family members, consisting of a signal sequence, a propeptide, a metalloproteinase domain, a disintegrin-like domain, a cysteine-rich region, and a variable number of TS-1 repeats. Expression analysis revealed that these ADAMTS genes are mainly expressed in fetal tissues, especially in lung (ADAMTS14, ADAMTS16, ADAMTS17, ADAMTS18, and ADAMTS19), kidney (ADAMTS14, ADAMTS15, and ADAMTS16), and liver (ADAMTS13, ADAMTS15 and ADAMTS18). Reverse transcriptase--polymerase chain reaction analysis also revealed the expression of some of these new ADAMTSs in different human adult tissues, such as prostate (ADAMTS13, ADAMTS17, and ADAMTS18), and brain (ADAMTS13, ADAMTS16, ADAMTS17, and ADAMTS18). High levels of ADAMTSs transcripts were also observed in some tumor biopsies and cells lines, including osteosarcomas (ADAMTS19), melanoma and colon carcinoma cells (ADAMTS13). Chromosomal location analysis indicated that the seven identified ADAMTS genes are dispersed in the human genome mapping to 9q34, 10q21, 11q25, 5p15, 15q24, 16q23, and 5q31, respectively. According to these results, together with a comparative analysis of ADAMTSs in other eukaryotic organisms, we conclude that these enzymes, with at least 18 distinct members encoded within the human genome, represent an example of a widely expanded protease family during metazoan evolution.

ADAM Proteins↗
PubMed2002

The presence of the WGD motif in CC8 heterodimeric disintegrin increases its inhibitory effect on alphaII(b)beta3, alpha(v)beta3, and alpha5beta1 integrins.

Two highly homologous dimeric disintegrins, CC5 and CC8, have been isolated from the venom of the North African sand viper Cerastes cerastes. CC5 is a homodimer containing an RGD motif in its subunits. CC8 is a heterodimer. The CC8A and CC8B subunits contain RGD and WGD tripeptide sequence in their respective integrin-binding loops. Both CC5 and CC8 inhibited platelet aggregation and the adhesion of cells expressing integrins alphaII(b)beta3, alpha(v)beta3, and alpha5beta1 to appropriate ligands. However, the inhibitory activity of CC8 was at least 1 order of magnitude higher than that of CC5. Enhanced activity of CC8 over CC5 was also observed in the induction of LIBS epitopes on beta1 and beta3 integrins. Synthetic peptides in which the arginyl residue of the RGD motif had been replaced with tryptophans exhibited increased inhibitory activity toward integrins alpha5beta1, alphaII(b)beta3, and alpha(v)beta3. Moreover, alanine substitution of the aspartic acid of the WGD motif of these peptides decreased their inhibitory ability, whereas the same substitution in the RGD sequence almost completely abolished the activity of the peptides. We conclude that the WGD motif enhances the inhibitory activity of disintegrins toward alphaII(b)beta3, alpha(v)beta3, and alpha5beta1 integrins.

Amino Acid Motifs↗
PubMed1999

Structure-function analysis of the ADAM family of disintegrin-like and metalloproteinase-containing proteins (review).

The ADAMs belong to a disintegrin-like and metalloproteinase-containing protein family that are zinc-dependent metalloproteinases. These proteins share all or some of the following domain structure: a signal peptide, a propeptide, a metalloproteinase, a disintegrin, a cysteine-rich, and an epidermal growth factor (EGF)-like domains, a transmembrane region, and a cytoplasmic tail. ADAMs are widely distributed in many organs, tissues, and cells, such as brain, testis, epididymis, ovary, breast, placenta, liver, heart, lung, bone, and muscle. These proteins are capable of four potential functions: proteolysis, adhesion, fusion, and intracellular signaling. Because the number of ADAM genes has grown rapidly and the biological functions of most members are unclear, this review analyzes the protein structures and functions, their activation and processing, their known and potential activities, and their evolutionary relationships. A sequence alignment of human ADAMs is compiled and their homology and physical data are calculated. The conceivable functions of ADAMs in reproduction, development, and diseases are also discussed.

Amino Acid Sequence↗
PubMed1997

Cloning of a disintegrin metalloproteinase that processes precursor tumour-necrosis factor-alpha.

Tumour-necrosis factor-alpha (TNF-alpha) is a cytokine that contributes to a variety of inflammatory disease states. The protein exists as a membrane-bound precursor of relative molecular mass 26K which can be processed by a TNF-alpha-converting enzyme (TACE), to generate secreted 17K mature TNF-alpha. We have purified TACE and cloned its complementary DNA. TACE is a membrane-bound disintegrin metalloproteinase. Structural comparisons with other disintegrin-containing enzymes indicate that TACE is unique, with noteable sequence identity to MADM, an enzyme implicated in myelin degradation, and to KUZ, a Drosophila homologue of MADM important for neuronal development. The expression of recombinant TACE (rTACE) results in the production of functional enzyme that correctly processes precursor TNF-alpha to the mature form. The rTACE provides a readily available source of enzyme to help in the search for new anti-inflammatory agents that target the final processing stage of TNF-alpha production.

ADAM Proteins↗
PubMed1995

Analysis of transcripts encoding novel members of the mammalian metalloprotease-like, disintegrin-like, cysteine-rich (MDC) protein family and their expression in reproductive and non-reproductive monkey tissues.

A number of sequence-related, cysteine-rich proteins containing metalloprotease-like and disintegrin-like domains (the MDC protein family), at least one of which has been shown to play a role in egg recognition during fertilization, are abundantly expressed in the mammalian male reproductive tract. In this paper we report the cloning and sequence analysis of three closely related isoforms of a novel member of this family which are expressed not only in the testis, but also in the liver, albeit at a lower level. Using a PCR-based approach we also demonstrate the presence of transcripts encoding additional, novel, disintegrin-containing proteins, in the liver and epididymis. We conclude that while some members of the MDC family are specific to the reproductive tract, suggesting functions peculiar to those tissues, others have a broader tissue distribution and may therefore play a more general role in integrin-mediated cell-cell recognition, adhesion or signalling.

ADAM Proteins↗