We next divided 46 single experiments into 3 groups depending on the dynamics observed in each experiment

May 5, 2017

activity in vivo are poorly understood. This is in part due to the complex composition and post-translational modification of PP2A. Structurally, it is a heterotrimeric complex typically consisting of a catalytic subunit , a scaffolding subunit and one of an array of different regulatory subunits. In mammalian cells, the A and C subunits each have two isoforms, which share high sequence similarity. However, the most variable component of the holoenzyme is the regulatory subunit, which can belong to one of four different families termed B, B9, B0 and B”’. Each one of these gene families encodes multiple isoforms and splice variants. The different families of B subunits bind to overlapping regions on the AC dimer so their association to the core enzyme is mutually exclusive. Combinatorially, this variety of B subunits could generate as many as 70 different holoenzyme assemblies. The current model for regulation of PP2A suggests that heterotrimers containing different regulatory subunits have distinct functions in vivo. More specifically, B subunits, which exhibit cell- and tissue-restricted expression, are considered to be a major determining factor of substrate specificity by, for example, targeting PP2A to different intracellular locations. For example, the B subfamily has been shown to target PP2A to microtubules while the B56 subfamily interacts with cyclin G and mediates PP2A functions in the Wnt/b-catenin and Erk signalling cascades. Further support for 10336422 this model stems 19770292 from recent three-dimensional structural information obtained for the AC core enzyme and the trimeric holoenzyme. The intrinsic flexibility of the A scaffolding subunit as well as Role of PME-1 in PP2A Function the AC core dimer, which experiences profound conformational rearrangements after binding of the regulatory subunit, has been proposed to be important for binding different regulatory subunits and for performing catalysis on a wide variety of substrates. A further level of PP2A regulation is provided by posttranslational modification of the catalytic subunit, which can be phosphorylated on Tyr307, as well as on a threonine residue. In addition, a unusual type of reversible methylation occurs at the carboxyl group of the C terminal Leu residue . Carboxylmethylation of Leu309 is catalysed by a specific S-adenosylmethionine dependent methyltransferase, termed leucine carboxylmethyltransferase . The demethylation Talampanel site reaction is catalysed by a specific PP2A methylesterase, which has been purified and molecularly characterized. Whereas phosphorylation of the catalytic subunit of PP2A inhibits enzyme activity, a link between methylation of Leu309 and PP2A activity has remained contentious with different groups observing opposed effects. The current generally accepted view is that methylation does not affect phosphatase activity in vitro, suggesting instead that this modification indirectly regulates PP2A activity by modulating the binding of different regulatory B subunits to AC dimers. By affecting the association of the C subunit with regulatory subunits in vivo, methylation is predicted to alter the targeting of PP2A to certain substrates and, as a consequence, potentially impact a wide range of signalling pathways. Consistent with this model, disruption of the major methyltransferase responsible for methylating PP2A in yeast leads to severe growth defects. On the other hand, deletion of the yeast PME-1 gene did not result in an observable cellular phenotype, even