Amino acid structure and characterization of a heterodimeric disintegrin from Vipera lebetina venom

Gasmi, Ammar; Srairi, Najet; Guermazi, Sami; Dkhil, Hafedh; Karoui, Hakim; Ayeb, Mohamed El

doi:10.1016/s0167-4838(01)00168-6

Cited by 40 publications

(32 citation statements)

References 23 publications

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“…Edman degradation of lebein-1 revealed two staggered N-terminal sequences, MNGSNPXXD and NGSNPXXD, at a 2:1 ratio. Except for the initial methionine residues, this sequence is identical to the published primary sequence of lebein (Swiss-Prot accession number P83253) (22). Furthermore, mass spectrometry determined its mass to be 14,083 Da and proved its identity to lebein.…”

Section: Recombinant Production Of a Solublementioning

confidence: 53%

“…One of them is the recently described lebein. Although it has been proposed to be a disintegrin for RGD-dependent integrins (22), we show in this work that lebein or lebein-1, as we refer to it, also avidly binds to the laminin-binding ␤ 1 integrins in an RGD-independent manner. In addition, we isolated a new disintegrin (lebein-2) with homology to lebein-1 and similar binding specificity.…”

mentioning

confidence: 50%

“…This may be the precursor of lebetase, a snake venom metalloproteinase that also possesses a disintegrin domain highly homologous to lebein-1 (22,27). Indeed, this band showed proteolytic activity in a gelatin zymogram (data not shown).…”

Section: Lebein-1 and Lebein-2 Inhibit Laminin-binding ␤ 1 Integrinsmentioning

confidence: 94%

“…4B) was identified as lebein, a recently discovered disintegrin (22), which we refer to as lebein-1. Edman degradation of lebein-1 revealed two staggered N-terminal sequences, MNGSNPXXD and NGSNPXXD, at a 2:1 ratio.…”

Section: Recombinant Production Of a Solublementioning

confidence: 99%

“…Interestingly, cell adhesion to immobilized fibronectin was even more severely compromised by both lebein-2 and lebein-1. Most likely, this was caused by RGD sequences that are located in both chains of lebein-1 (22). The complete primary structure of lebein-2 (and hence the presence of RGD sequences within lebein-2) is not known yet.…”

Section: Lebein-1 and Lebein-2 Inhibit Laminin-binding ␤ 1 Integrinsmentioning

confidence: 99%

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Vipera lebetina Venom Contains Two Disintegrins Inhibiting Laminin-binding β1 Integrins

Eble

Brückner

Mayer

2003

Journal of Biological Chemistry

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To explain the myotoxic effects of snake venoms, we searched for inhibitors of ␣ 7 ␤ 1 integrin, the major laminin-binding integrin in skeletal muscle. We discovered two inhibitors in the venom of Vipera lebetina. One of them, lebein-1 (known as lebein), has already been proposed to be a disintegrin because of its RGD-containing primary sequence. The other, lebein-2, is a novel protein that also interacts firmly with ␣ 3 ␤ 1 , ␣ 6 ␤ 1 , and ␣ 7 ␤ 1 integrins, but not with the collagen-binding ␣ 1 ␤ 1 and ␣ 2 ␤ 1 integrins. Ligand binding of laminin-recognizing ␤ 1 integrins was efficiently blocked by both lebein-1 and lebein-2. In cell attachment assays, lebein-1 and lebein-2 inhibited myoblast attachment not only to laminin, but also to fibronectin. However, neither lebein-1 nor lebein-2 interacted with ␣ 7 ␤ 1 integrin in an RGD-dependent manner, similar to the interaction of the laminin with ␣ 7 ␤ 1 integrin. Identical divalent cation dependence of integrin binding to laminin and to either of the two inhibitors and their mutually exclusive binding suggest that both lebein-1 and lebein-2 interact with the ligandbinding site of laminin-binding ␤ 1 integrins by mimicking the yet unknown integrin-binding structure of laminins. Like lebein-1, lebein-2 is a soluble heterodimeric disintegrin of low molecular mass. Together with membrane-bound ADAM-2 and ADAM-9, the two inhibitors seem to form a small group of disintegrins that can bind to laminin-binding ␤ 1 integrins. Because of their inhibitory capability both in vitro and in vivo, lebein-1 and lebein-2 may be valuable tools in influencing laminininduced, integrin-mediated cell functions such as cell anchorage, migration, and mechanical force transduction on laminin-rich basement membranes.

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Section: Recombinant Production Of a Solublementioning

confidence: 53%

mentioning

confidence: 50%

Section: Lebein-1 and Lebein-2 Inhibit Laminin-binding ␤ 1 Integrinsmentioning

confidence: 94%

Section: Recombinant Production Of a Solublementioning

confidence: 99%

Section: Lebein-1 and Lebein-2 Inhibit Laminin-binding ␤ 1 Integrinsmentioning

confidence: 99%

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Vipera lebetina Venom Contains Two Disintegrins Inhibiting Laminin-binding β1 Integrins

Eble

Brückner

Mayer

2003

Journal of Biological Chemistry

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Lebein, a snake venom disintegrin, suppresses human colon cancer cells proliferation and tumor-induced angiogenesis through cell cycle arrest, apoptosis induction and inhibition of VEGF expression

et al. 2016

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Lebein, is an heterodimeric disintegrin isolated from Macrovipera lebetina snake venom that was previously characterized as an inhibitor of ADP-induced platelet aggregation. In this study, we investigated the effect of Lebein on the p53-dependent growth of human colon adenocarcinoma cell lines. We found that Lebein significantly inhibited LS174 (p53wt), HCT116 (p53wt), and HT29 (p53mut) colon cancer cell viability by inducing cell cycle arrest through the modulation of expression levels of the tumor suppression factor p53, cell cycle regulating proteins cyclin D1, CDK2, CDK4, retinoblastoma (Rb), CDK1, and cyclin-dependent kinase inhibitors p21 and p27. Interestingly, Lebein-induced apoptosis of colon cancer cells was dependent on their p53 status. Thus, in LS174 cells, cell death was associated with PARP cleavage and the activation of caspases 3 and 8 while in HCT116 cells, Lebein induced caspase-independent apoptosis through increased expression of apoptosis inducing factor (AIF). In LS174 cells, Lebein triggers the activation of the MAPK ERK1/2 pathway through induction of reactive oxygen species (ROS). It also decreased cell adhesion and migration to fibronectin through down regulation of α5β1 integrin. Moreover, Lebein significantly reduced the expression of two angiogenesis stimulators, Vascular Endothelial Growth Factor (VEGF) and Neuropilin 1 (NRP1). It inhibited the VEGF-induced neovascularization process in the quail embryonic CAM system and blocked the development of human colon adenocarcinoma in nude mice. Overall, our work indicates that Lebein may be useful to design a new therapy against colon cancer. © 2016 Wiley Periodicals, Inc.

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Snake venomics: Comparative analysis of the venom proteomes of the Tunisian snakesCerastes cerastes, Cerastes vipera andMacrovipera lebetina

et al. 2005

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The protein composition of the crude venoms of the three most important vipers of Tunisia was analyzed by RP-HPLC, N-terminal sequence analysis, MALDI-TOF mass determination, and in-gel tryptic digestion followed by PMF and CID-MS/MS of selected peptide ions in a quadrupole-linear IT instrument. Our results show that the venom proteomes of Cerastes cerastes, Cerastes vipera, and Macrovipera lebetina are composed of proteins belonging to a few protein families. However, each venom showed distinct degree of protein composition complexity. The three venoms shared a number of protein classes though the relative occurrence of these toxins was different in each snake species. On the other hand, the venoms of the Cerastes species and Macrovipera lebetina each contained unique components. The comparative proteomic analysis of Tunisian snake venoms provides a comprehensible catalogue of secreted proteins, which may contribute to a deeper understanding of the biological effects of the venoms, and may also serve as a starting point for studying structure-function correlations of individual toxins.

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Amino acid structure and characterization of a heterodimeric disintegrin from Vipera lebetina venom

Cited by 40 publications

References 23 publications

Vipera lebetina Venom Contains Two Disintegrins Inhibiting Laminin-binding β1 Integrins

Vipera lebetina Venom Contains Two Disintegrins Inhibiting Laminin-binding β1 Integrins

Lebein, a snake venom disintegrin, suppresses human colon cancer cells proliferation and tumor-induced angiogenesis through cell cycle arrest, apoptosis induction and inhibition of VEGF expression

Snake venomics: Comparative analysis of the venom proteomes of the Tunisian snakesCerastes cerastes, Cerastes vipera andMacrovipera lebetina

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