A 28-kDa Protein with Disintegrin-like Structure (Jararhagin-C) Purified from Bothrops jararaca Venom Inhibits Collagen- and ADP-Induced Platelet Aggregation

Usami, Yoshiko; Fujimura, Yoshihiro; Miura, S.; Shima, Hiroko; Yoshida, Eri; Yoshioka, Akira; Hirano, Kazuyuki; Suzuki, Masami; Titani, Koiti

doi:10.1006/bbrc.1994.1706

Cited by 137 publications

(78 citation statements)

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“…metastasis). The snake venom metalloprotease/disintegrin jararhagin is known to block collagen-induced aggregation of platelets (46). It has been proposed that the inhibition of platelet response to collagen by jararhagin is mediated through the binding of jararhagin to the platelet ␣2-subunit via the disintegrin domain followed by proteolysis of the ␤1 subunit with loss of the integrin structure (conformation) necessary for the binding of macromolecular ligands (47).…”

Section: Discussionmentioning

confidence: 99%

Specific Interaction of the Recombinant Disintegrin-like Domain of MDC-15 (Metargidin, ADAM-15) with Integrin αvβ3

Zhang

Kamata

Yokoyama

et al. 1998

Journal of Biological Chemistry

202

208

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MDC-15 (ADAM-15, metargidin), a membrane-anchored metalloprotease/disintegrin/cysteine-rich protein, is expressed on the surface of a wide range of cells and has an RGD tripeptide in its disintegrin-like domain. MDC-15 is potentially involved in cell-cell interactions through its interaction with integrins. We expressed a recombinant MDC-15 disintegrin-like domain as a fusion protein with glutathione S-transferase (designated D-15) in bacteria and examined its binding function to integrins using mammalian cells expressing different recombinant integrins. We found that D-15 specifically interacts with ␣v␤3 but not with the other integrins tested (␣2␤1, ␣3␤1, ␣4␤1, ␣5␤1, ␣6␤1, ␣6␤4, ␣v␤1, ␣IIb␤3, and ␣L␤2). Mutation of the tripeptide RGD to SGA totally blocked binding of D-15 to ␣v␤3, suggesting that D-15-␣v␤3 interaction is RGD-dependent. When the sequence RPTRGD is mutated to NWKRGD, D-15 is recognized by both ␣IIb␤3 and ␣v␤3, suggesting that the receptor binding specificity is mediated by the sequence flanking the RGD tripeptide, as in snake venom disintegrins. These results indicate that the disintegrin-like domain of MDC-15 functions as an adhesion molecule and may be involved n ␣v␤3-mediated cell-cell interactions.Metalloprotease/disintegrin/cysteine-rich proteins (MDCs, also called ADAMs) 1 are membrane-anchored proteins with several domains including a metalloprotease domain, a disintegrin-like domain, a cysteine-rich sequence, an epidermal growth factor-like sequence, a transmembrane domain, and a short cytoplasmic domain (1). The biological functions of MDCs are not clear; however, we do know that fertilins (MDC-1 and -2) (2) are involved in sperm-egg binding and fusion (3), meltrins (MDC-12) (4) are involved in myoblast fusion during muscle development, and KUZ (a Drosophila MDC protein) (5) assists in neurogenesis. The MDC cytoplasmic domain has a proline-rich potential SH3 binding motif, suggesting that MDCcounter receptor interaction may induce signal transduction.Integrins are a family of cell adhesion receptors that bind to a variety of ligands, including extracellular matrix proteins and other cell surface molecules (6 -10). MDCs are potential ligands for integrins, since most snake venom disintegrins interact with integrins ␣IIb␤3 and ␣v␤3 (reviewed in Ref. 11 and references therein). However, little is known about the receptor specificity of MDCs, except that mouse egg integrin ␣6␤1 has been proposed as a receptor for fertilin (2). Evans et al. (12) recently expressed recombinant fertilin fragments in bacteria as fusion proteins with maltose-binding protein (12). The recombinant fertilin-␤ fragment has been shown to bind to the egg membrane to which sperm bind and to block sperm from binding to the egg. These results suggest that the disintegrinlike domains of MDCs may be properly folded in bacteria, that glycosylation of the disintegrin-like domain may not be required for interaction with receptors, and that a strategy using recombinant MDC proteins is a viable alternative to those using puri...

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Section: Discussionmentioning

confidence: 99%

Specific Interaction of the Recombinant Disintegrin-like Domain of MDC-15 (Metargidin, ADAM-15) with Integrin αvβ3

Zhang

Kamata

Yokoyama

et al. 1998

Journal of Biological Chemistry

202

208

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“…2 Another region of functional interest corresponds to the disintegrin loops within the cysteine-rich domain. This loop is found in members of the reprolysin subfamily of metalloproteases (35,36). The disintegrin motif consists of 13-15 amino acids, which can contain an RGD (or RGX) motif with a negatively charged residue at the X position.…”

Section: Table I Effect Of Meth-1 and Truncated Fragments Of Meth-1 Amentioning

confidence: 99%

METH-1, a Human Ortholog of ADAMTS-1, and METH-2 Are Members of a New Family of Proteins with Angio-inhibitory Activity

Vázquez¹,

Hastings²,

Ortega³

et al. 1999

Journal of Biological Chemistry

391

331

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We have studied two related proteins that contain a repeated amino acid motif homologous to the anti-angiogenic type 1 repeats of thrombospondin-1 (TSP1). Complete sequence analysis revealed no other similarities with TSP1, but identified unique signal sequences, as well as metalloprotease and disintegrin-like domains in the NH 2 termini. We named these proteins METH-1 and METH-2 due to the novel combination of metalloprotease and thrombospondin domains. Overall amino acid sequence identity between METH-1 and METH-2 is 51.7%, yet transcript distribution revealed non-overlapping patterns of expression in tissues and cultured cell lines. To characterize these proteins functionally, we isolated full-length cDNAs, produced recombinant protein, and generated antisera to the recombinant proteins. Both METH-1 and METH-2 represent single copy genes, which encode secreted and proteolytically processed proteins. METH proteins suppressed fibroblast growth factor-2-induced vascularization in the cornea pocket assay and inhibited vascular endothelial growth factor-induced angiogenesis in the chorioallantoic membrane assay. Suppression of vessel growth in both assays was considerably greater than that mediated by either thrombospondin-1 or endostatin on a molar basis. Consistent with an endothelial specific response, METH-1 and METH-2 were shown to inhibit endothelial cell proliferation, but not fibroblast or smooth muscle growth. We propose that METH-1 and METH-2 represent a new family of proteins with metalloprotease, disintegrin, and thrombospondin domains. The distinct distribution of each gene product suggests that each has evolved distinct regulatory mechanisms that potentially allow for fine control of activity during distinct physiological and pathological states. Thrombospondin-1 (TSP1)1 is a modular protein that associates with the extracellular matrix and has the ability to inhibit angiogenesis in vivo (1, 2). Under culture conditions, TSP1 blocks capillary-like tube formation (3) and endothelial cell proliferation (4). The region responsible for the anti-angiogenic activity has been mapped to the 385-522 amino acid region of the protein, which contains three type 1 (properdin or TSP) repeats (2). Recombinant and proteolytic fragments containing these repeats exhibited angio-inhibitory activity in the rabbit corneal pocket and chorioallantoic membrane assays (2, 5, 6) and peptides derived from the second and third type 1 repeats of TSP1 inhibit endothelial cell chemotaxis and proliferation (7). Furthermore, peptides derived from the same region induce apoptosis of endothelial cells and suppress tumor growth when injected systemically (8, 9). Of the five known members of the TSP family, only TSP1 and TSP2 contain type 1 repeats, and are the only members that inhibit angiogenesis (10, 11). We hypothesized that TSP/type 1 repeats might be present in other yet unidentified proteins, in a context that enables activity as inhibitors of capillary growth. We therefore initiated a search for novel cDNAs using the anti-angio...

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“…Na mesma posição ocupada por esta seqüência também é encontrada a seqüência K-G-D (Lys-Gly-Asp) em algumas disintegrinas, como a barbourina, isolada de Sistrurus barbouri (USAMI et al, 1994;SCARBOROUGH et al, 1991). O domínio tipo-disintegrina apresenta em posição análoga àquela ocupada pela seqüência RGD, a seqüência E-C-D (Glu-Cys-Asp), à qual também foi atribuída a função de interagir com integrinas CALVETE et al, 2005).…”

Section: Metaloproteinases De Venenos De Serpentesunclassified

“…jararaca, e chamada de jararhagina-C por Usami et al (1994). Esta proteína é gerada pela autólise de proteinases como a jararhagina (MOURA-DA-SILVA et al,…”

Section: Domínios Não Catalíticos Das Metaloproteinasesunclassified

“…Tanto a jararhagina-C, como a catrocollastatina C, inibem a agregação plaquetária induzida pelo colágeno (USAMI et al, 1994;SHIMOKAWA et al, 1997). A jaracetina, um dímero de 60 kDa, que representa uma forma diferentemente processada da jararhagina, interage com o domínio A1 do vWF e também bloqueia a adesão de plaquetas ao colágeno (DE LUCA et al, 1995).…”

Section: Domínios Não Catalíticos Das Metaloproteinasesunclassified

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Estudo sobre a função dos domínios não catalíticos do HF3, uma metaloproteínase do veneno da serpente Bothrops jararaca, na sua interação com alvos celulares e plasmáticos.

Santos¹

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A 28-kDa Protein with Disintegrin-like Structure (Jararhagin-C) Purified from Bothrops jararaca Venom Inhibits Collagen- and ADP-Induced Platelet Aggregation

Cited by 137 publications

References 0 publications

Specific Interaction of the Recombinant Disintegrin-like Domain of MDC-15 (Metargidin, ADAM-15) with Integrin αvβ3

Specific Interaction of the Recombinant Disintegrin-like Domain of MDC-15 (Metargidin, ADAM-15) with Integrin αvβ3

METH-1, a Human Ortholog of ADAMTS-1, and METH-2 Are Members of a New Family of Proteins with Angio-inhibitory Activity

Estudo sobre a função dos domínios não catalíticos do HF3, uma metaloproteínase do veneno da serpente Bothrops jararaca, na sua interação com alvos celulares e plasmáticos.

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