PPase_methylesterase_euk

Family: PPase_methylesterase_euk

Block: X

Parent Family: Abhydrolase_6

Comment

PIRSF022950 This group represents protein phosphatase methylesterase, eukaryotic type. Carboxymethylation of proteins is a highly conserved means of regulation in eukaryotic cells. The protein phosphatase 2A (PP2A) catalytic (C) subunit is reversibly methylated at its carboxyl terminus by specific methyltransferase and methylesterase enzymes. Protein phosphatase 2A (PP2A) is an important serine/threonine phosphatase that plays a role in many biological processes. Reversible carboxyl methylation of the PP2A catalytic subunit is an essential regulatory mechanism for its function. Demethylation and negative regulation of PP2A is mediated by a PP2A-specific methylesterase PME-1, which is conserved from yeast to humans. PME-1 directly binds to the active site of PP2A. This interaction results in the activation of PME-1 by rearranging the catalytic triad into an active conformation. Interactions also lead to inactivation of PP2A by evicting the manganese ions required for the phosphatase activity (Xing et al. ). PPME proteins show false positive hits with the prosite PS00120 of lipases. PME-1 S156A and M335D knock-in mice deficient in methylesterase and PP2A inhibitory activity, respectively showed phenotypes distinct from the perinatal lethality of PME-1 null mice. The loss of methylesterase activity due to the S156A mutation resulted in systemic apoptosis characterized by brain atrophy: the layers of the cerebellum collapsed with fewer Purkinje cells and more microglia. M335D mutant pups did not appear deformed and had intact brains but died about two days after birth with a demonstrated loss of olfaction and apoptosis in the olfactory epithelium (Ikeda et al. )