PIVL, a new serine protease inhibitor from Macrovipera lebetina transmediterranea venom, impairs motility of human glioblastoma cells

A novel Kunitz-type serine proteinase inhibitor, termed PIVL, was purified to homogeneity from the venom of the Tunisian snake Macrovipera lebetina transmediterranea. It is a monomeric polypeptide chain cross-linked by three disulfide linkages with an isotope-averaged molecular mass of 7691.7Da. The...

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Bibliographic Details
Published in:Matrix biology 2013-01, Vol.32 (1), p.52-62
Main Authors: Morjen, Maram, Kallech-ziri, Olfa, Bazaa, Amine, Othman, Houcemeddine, Mabrouk, Kamel, Zouari-kessentini, Raoudha, Sanz, Libia, Calvete, Juan José, Srairi-Abid, Najet, El Ayeb, Mohamed, Luis, José, Marrakchi, Naziha
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Amino Acid Motifs - genetics
Amino Acid Sequence
Animals
Base Sequence
cDNA cloning
Cell Adhesion
Cell Adhesion - drug effects
Cell Line, Tumor
Cell motility
Cell Movement
Cell Movement - drug effects
Chromatography, High Pressure Liquid
Cloning, Molecular
DNA Primers
DNA Primers - genetics
DNA, Complementary
DNA, Complementary - genetics
Dose-Response Relationship, Drug
Humans
Integrin
Integrin alphaVbeta3
Integrin alphaVbeta3 - antagonists & inhibitors
Kunitz-type serine protease inhibitor
Lethal Dose 50
Microscopy, Video
Models, Molecular
Molecular Sequence Data
Peptides
Peptides - chemistry
Peptides - genetics
Peptides - isolation & purification
Peptides - pharmacology
Peptides - toxicity
Protein Conformation
Sequence Alignment
Sequence Analysis, DNA
Serine Proteinase Inhibitors
Serine Proteinase Inhibitors - chemistry
Serine Proteinase Inhibitors - genetics
Serine Proteinase Inhibitors - isolation & purification
Serine Proteinase Inhibitors - pharmacology
Serine Proteinase Inhibitors - toxicity
Snake venom
Tandem Mass Spectrometry
Time-Lapse Imaging
Tunisia
Viper Venoms
Viper Venoms - chemistry
Viperidae
Viperidae - metabolism
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Summary:A novel Kunitz-type serine proteinase inhibitor, termed PIVL, was purified to homogeneity from the venom of the Tunisian snake Macrovipera lebetina transmediterranea. It is a monomeric polypeptide chain cross-linked by three disulfide linkages with an isotope-averaged molecular mass of 7691.7Da. The 67-residue full-length PIVL sequence was deduced from a venom gland cDNA clone. Structurally, PIVL is built by a single Kunitz/BPTI-like domain. Functionally, it is able to specifically inhibit trypsin activity. Interestingly, PIVL exhibits an anti-tumor effect and displays integrin inhibitory activity without being cytotoxic. Here we show that PIVL is able to dose-dependently inhibit the adhesion, migration and invasion of human glioblastoma U87 cells. Our results also show that PIVL impairs the function of αvβ3 and to a lesser extent, the activity of αvβ6, αvβ5, α1β1 and α5β1 integrins. Interestingly, we demonstrate that the 41RGN43 motif of PIVL is likely responsible for its anti-cancer effect. By using time lapse videomicroscopy, we found that PIVL significantly reduced U87 cells motility and affected cell directionality persistence by 68%. These findings reveal novel pharmacological effects for a Kunitz-type serine proteinase inhibitor. ► PIVL, a new serine protease inhibitor was isolated from snake venom. ► It was able to inhibit specifically trypsin activity. ► PIVL exhibited an anti-tumor effect and displayed an anti-integrin activity. ► We demonstrate that the 41RGN43 motif of PIVL is likely responsible for this effect.
ISSN:0945-053X
1569-1802
DOI:10.1016/j.matbio.2012.11.015