Protein phosphatase 2A methylesterase-1 (PME-1)

Protein phosphatase 2A methylesterase-1 (PME-1) is a highly conserved enzyme from yeast to humans that serves as the specific methylesterase for protein phosphatase 2A (PP2A). PME-1 catalyzes the demethylation of the C-terminal leucine residue of the PP2A catalytic subunit, representing an essential regulatory mechanism for PP2A function. Crystal structure studies have revealed that PME-1 directly binds to the active site of PP2A, which triggers two important events: the rearrangement of PME-1's catalytic triad into an active conformation for demethylation activity, and the simultaneous inactivation of PP2A through eviction of manganese ions necessary for its phosphatase activity. This dual functionality positions PME-1 as a critical regulator of PP2A activation state, methylation status, and holoenzyme assembly in cells. PME-1 plays important roles in cell survival and has emerged as a druggable target for cancer therapy. The enzyme's ability to negatively regulate PP2A, which itself is a major serine/threonine phosphatase involved in numerous cellular processes including cell cycle regulation, growth, differentiation, and neuronal function, makes PME-1 an attractive target for pharmaceutical intervention in diseases where PP2A activity is dysregulated, particularly in cancer and neurodegenerative diseases such as Alzheimer's disease.

Other names

PME-1PP2A-specific methylesteraseprotein methylesterase-1PP2A methylesterase

PME-1 acts as a PP2A-specific methylesterase that catalyzes the demethylation of the PP2A catalytic subunit at its C-terminal leucine residue. It has a dual mechanism: first, it directly binds to the active site of PP2A and undergoes conformational activation of its own catalytic triad; second, this binding simultaneously inactivates PP2A by evicting manganese ions required for phosphatase activity. This dual role regulates PP2A activation, methylation status, and holoenzyme assembly.