Identification of ATP-synthase as a novel intracellular target for microcystin-LR.
Microcystins (MCs) are a group of closely related cyclic heptapeptides produced by a variety of common cyanobacteria. These are potent and highly specific hepatotoxins, the toxicity of which is based upon their inhibition of type-1 (PP1) and type-2A (PP2A) protein phosphatases. Apart from protein phosphatases, it is not known whether these phosphatase-inhibiting peptides could bind any other cellular proteins. We wanted to determine whether any possible unknown MC-adducts could explain the apoptotic effects observed at high concentrations of MCs. The question of other possible cellular proteins binding to MCs is also relevant when these compounds are employed for affinity purification of protein phosphatases. In MC-treated cell lysates, antibodies to MC recognized three protein adducts of 35-37 and 55 kD. By immunochemical and proteomics approaches, these proteins were identified as the catalytic subunits of type-1 and type-2A protein phosphatases and the ATP-synthase beta-subunit. The latter target could be associated with the suggested apoptosis-inducing potential of MCs.
Mikhailov
Andrey
A
Turku Center for Biotechnology, POB 123, FIN-20521 Turku, Finland.
Härmälä-Braskén
Ann-Sofi
AS
Hellman
Jukka
J
Meriluoto
Jussi
J
Eriksson
John E
JE
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008387:Marine Toxins; D052998:Microcystins; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors; D021122:Protein Subunits; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D051381:Rats
D004791:Enzyme Inhibitors; D008387:Marine Toxins; D052998:Microcystins; D010456:Peptides, Cyclic; D021122:Protein Subunits; D010749:Phosphoprotein Phosphatases; D006180:Proton-Translocating ATPases; C057862:cyanoginosin LR