The novel metalloproteinase atroxlysin-I from Peruvian Bothrops atrox (Jergón) snake venom acts both on blood vessel ECM and platelets.
We report the isolation and structure-function relationship of a 23kDa metalloproteinase named atroxlysin-I from the venom of the Peruvian Bothrops atrox (Jergón). Atroxlysin is a P-I metalloproteinase and contains 204 residues. Its proteolytic activity towards dimethylcasein is enhanced by Ca2+ but inhibited by EDTA, dithiothreitol, excessive Zn2+ and alpha2-macroglobulin. Unlike other structurally homologous P-I metalloproteinases, atroxlysin-I causes hemorrhages. To examine its hemorrhagic activity mechanistically, we studied its function in vitro and in vivo. It cleaved the Ala14-Leu15 and Tyr16-Leu17 bonds in oxidized insulin B-chain and specifically hydrolyzed the alpha-chains of fibrin(ogen) in a dose- and time-dependent manner. Atroxlysin-I cleaved plasma fibronectin and other extracellular matrix proteins (collagens I and IV) and the triple-helical fragment CB3 of collagen IV, but did not degrade laminin-111. Complementarily, the laminin and collagen binding integrins alpha7beta1 and alpha1beta1 were cleaved by atroxlysin. Even without catalytic activity atroxlysin-I inhibited collagen- and ADP-triggered platelet aggregation.
Sanchez
Eladio F
EF
Research and Development Center, Ezequiel Dias Foundation, 30510-010 Belo Horizonte, Brazil. eladiooswaldo@gmail.com
Schneider
Francisco S
FS
Yarleque
Armando
A
Borges
Marcia H
MH
Richardson
Michael
M
Figueiredo
Suely G
SG
Evangelista
Karla S
KS
Eble
Johannes A
JA
D000595:Amino Acid Sequence; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D001808:Blood Vessels / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D017837:Bothrops; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006470:Hemorrhage / Q000139:chemically induced; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D016023:Integrins / Q000378:metabolism; D008259:Macroglobulins / Q000378:metabolism; D045726:Metalloproteases / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D008969:Molecular Sequence Data; D012910:Snake Venoms / Q000201:enzymology*; D013379:Substrate Specificity
D005353:Fibronectins; D016023:Integrins; D008259:Macroglobulins; D012910:Snake Venoms; D005337:Fibrin; D005340:Fibrinogen; D045726:Metalloproteases