A novel metalloprotease from Gloydius halys venom induces endothelial cell apoptosis through its protease and disintegrin-like domains.
A novel hemorrhagic metalloprotease, halysase, isolated from the snake venom of Gloydius halys induces apoptosis in endothelial cells. The purified metalloprotease is a monomeric glycoprotein with an isoelectric point of 4.8. Analysis of the cDNA sequence encoding halysase revealed that the enzyme consists of multifunctional domains including a proprotein domain, a protease domain, a disintegrin-like domain and a cysteine-rich domain. The metalloprotease has a DECD sequence in the disintegrin-like domain instead of the typical RGD sequence. Halysase strongly inhibits proliferation of human umbilical vein endothelial cells in a dose-dependent manner as well as adhesion of the cells to extracellular matrix proteins. The enzyme specifically hydrolyzes not only extracellular matrix proteins such as fibronectin, vitronectin, and type IV collagen, but also integrins alpha1beta1 and alpha5beta1. The apoptosis of endothelial cells induced by halysase is closely associated with activation of caspase-3 and decreased level of Bcl-X(L)/Bax. Apohalysase, which lacks metalloprotease activity, is also able to induce the apoptosis. Several lines of experimental evidence suggest that the protease domain and the disintegrin-like domain of halysase cooperatively contribute to the induction of endothelial cell apoptosis.
You
Weon-Kyoo
WK
Dept. of Biochemistry, College of Science, Yonsei University, Seoul 120-749, Korea.
Seo
Hyun-Ji
HJ
Chung
Kwang-Hoe
KH
Kim
Doo-Sik
DS
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003001:Cloning, Molecular; D003435:Crotalid Venoms / Q000201:enzymology*; D018076:DNA, Complementary / Q000235:genetics; D019483:Disintegrins / Q000737:chemistry*; D010450:Endopeptidases / Q000737:chemistry*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008666:Metalloendopeptidases; D045726:Metalloproteases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid
D003435:Crotalid Venoms; D018076:DNA, Complementary; D019483:Disintegrins; D016023:Integrins; D016222:Fibroblast Growth Factor 2; D010450:Endopeptidases; D045726:Metalloproteases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D008666:Metalloendopeptidases; C508062:halysase, Gloydius halys