Carboxyl methylation of the phosphoprotein phosphatase 2A catalytic subunit promotes its functional association with regulatory subunits in vivo

The phosphoprotein phosphatase 2A (PP2A) catalytic subunit contains a methy l ester on its C-terminus, which in mammalian cells is added by a specific carboxyl methyltransferase and removed by a specific carboxyl methylesteras e. We have identified genes in yeast that show significant homology to huma n carboxyl methyltransferase and methylesterase. Extracts of wild-type yeas t cells contain carboxyl methyltransferase activity, while extracts of stra ins deleted for one of the methyltransferase genes, PPM1, lack all activity . Mutation of PPM1 partially disrupts the PP2A holoenzyme in vivo and ppm1 mutations exhibit synthetic lethality with mutations in genes encoding the B or B' regulatory subunit. Inactivation of PPM1 or overexpression of PPE1, the yeast gene homologous to bovine methylesterase, yields phenotypes simi lar to those observed after inactivation of either regulatory subunit. Thes e phenotypes can be reversed by overexpression of the B regulatory subunit. These results demonstrate that Ppm1 is the sole PP2A methyltransferase in yeast and that its activity is required for the integrity of the PP2A holoe nzyme.