complex(p(HGNC:PPP2CA), p(HGNC:PPP2R1A), p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55"))

Components

• p(HGNC:PPP2CA)
• p(HGNC:PPP2R1A)
• p(INTERPRO:"Protein phosphatase 2A regulatory subunit PR55")

To gain full activity towards specific substrates, the PP2A core enzyme interacts with a variable regulatory subunit to form a heterotrimeric holoenzyme. The variable regulatory subunits consist of four families: B (also known as B55 or PR55), B′ (B56 or PR61), B′′ (PR48/PR72/PR130), and B′′′ (PR93/PR110), with at least 16 members in these families PubMed:19277525

Except the B′′′ subunits, direct interactions between the PP2A core enzyme and the regulatory subunits have been demonstrated PubMed:19277525

Structure of the heterotrimeric PP2A holoenzyme involving a regulatory B subunit (Figure 2D) reveals how B subunit specifically recognizes the PP2A core enzyme and how it may facilitate substrate dephosphorylation PubMed:19277525

In fact, competition experiments using recombinant proteins suggested that, compared to the unmethylated form, the methylated PP2A core enzyme exhibited a higher binding affinity for the B subunit PubMed:19277525

In fact, competition experiments using recombinant proteins suggested that, compared to the unmethylated form, the methylated PP2A core enzyme exhibited a higher binding affinity for the B subunit PubMed:19277525

By contrast, several recent studies using purified, recombinant proteins showed that the methylation status of the catalytic subunit did not play a decisive role for the in vitro assembly of PP2A holoenzymes involving the B and B′ subunit PubMed:19277525

Methylation of the carboxy-terminal Leu309 in a conserved TPDYFL309 motif of the catalytic subunit has been shown to enhance the affinity of the PP2A core enzyme for some, but not all, regulatory subunits PubMed:19277525

Neither mutation of the carboxy-terminal Leu residue nor removal of the carboxy-terminal 14 amino acids of the catalytic subunit prevented formation of heterotrimeric holoenzymes involving the B or B′ subunits PubMed:19277525

Notably, the loss of neuronal PP2A/Bα holoenzymes correlates with the down-regulation of PP2A methylation and severity of phosphorylated tau (P-tau) pathology in AD-affected brain regions (Sontag et al.,2004 a,b). PubMed:24653673

As described earlier, it is especially significant that the biogenesis of PP2A/Bα holoenzymes is intimately related to the methylation state of PP2A PubMed:24653673

The deregulation of PP2A methylation in AD is especially interesting, not only because it can lead to a loss of PP2A/Bα, a major tau regulator, but also because PP2A methylation state is intimately linked to the integrity of one-carbon metabolism, which regulates SAM supply (Reviewed in Fowler,2005). PubMed:24653673

This is potentially physiologically significant since phosphorylation of tau at Thr-231, a target site for ERK2, GSK3β, and cdk5, occurs early in AD and can further inhibit the ability of PP2A/Bα to dephosphorylate other major AD-tau phosphoepitopes (Landrieu et al.,2011). PubMed:24653673

Significantly, downregulation of LCMT1 expression leads to a significant decrease of PP2A methylation and concomitant loss of PP2A holoenzymes containing the regulatory Bα (or PPP2R2A) subunit (PP2A/Bα; Lee and Pallas,2007; Sontag et al.,2008; MacKay et al.,2013). PubMed:24653673

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

The deregulation of PP2A methylation in AD is especially interesting, not only because it can lead to a loss of PP2A/Bα, a major tau regulator, but also because PP2A methylation state is intimately linked to the integrity of one-carbon metabolism, which regulates SAM supply (Reviewed in Fowler,2005). PubMed:24653673

The specificity in this in vitro system is quite robust, as evidenced by the observation that the PP2A core enzyme exhibited a lower activity to dephosphorylate the Tau protein than the PP2A holoenzyme involving the B subunit, but a higher activity than the holoenzyme involving the B′ subunit PubMed:19277525

Of particular relevance to the Alzheimer’s disease (AD) field, PP2A/Bα holoenzymes can directly bind to the microtubule-associated protein tau (Sontag et al.,1999, 2012; Xu et al.,2008). PubMed:24653673

It is noteworthy that PP2A/Bα can directly bind to tau via a domain encompassing the microtubule-binding of tau; this interaction maximizes the efficiency of tau dephosphorylation by PP2A (Sontag et al.,1999; Xu et al.,2008; Figure 3A). PubMed:24653673

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

Notably, the loss of neuronal PP2A/Bα holoenzymes correlates with the down-regulation of PP2A methylation and severity of phosphorylated tau (P-tau) pathology in AD-affected brain regions (Sontag et al.,2004 a,b). PubMed:24653673

As described earlier, it is especially significant that the biogenesis of PP2A/Bα holoenzymes is intimately related to the methylation state of PP2A PubMed:24653673

The deregulation of PP2A methylation in AD is especially interesting, not only because it can lead to a loss of PP2A/Bα, a major tau regulator, but also because PP2A methylation state is intimately linked to the integrity of one-carbon metabolism, which regulates SAM supply (Reviewed in Fowler,2005). PubMed:24653673

While many PP2A holoenzymes have the potential to indirectly affect tau phosphorylation by modulating key tau protein kinases (For example see Louis et al., 2011), biochemical and structural studies have demonstrated that PP2A/Bα is the primary PP2A isoform that mediates tau dephosphorylation (Sontag et al.,1996, 1999; Xu et al.,2008). PubMed:24653673

Specific inhibition of PP2A/Bα is associated with enhanced tau phosphorylation at many AD-like phospho epitopes, and subsequent inability of tau to bind to and stabilize microtubules (Sontag et al., 1996). PubMed:24653673

Specific inhibition of PP2A/Bα is associated with enhanced tau phosphorylation at many AD-like phospho epitopes, and subsequent inability of tau to bind to and stabilize microtubules (Sontag et al., 1996). PubMed:24653673

Deregulation of PP2A/Bα alone also affects microtubule stability (Nunbhakdi-Craig et al., 2007) and neurite outgrowth (Sontag et al.,2010) in neuroblastoma cells PubMed:24653673

Deregulation of PP2A/Bα alone also affects microtubule stability (Nunbhakdi-Craig et al., 2007) and neurite outgrowth (Sontag et al.,2010) in neuroblastoma cells PubMed:24653673

Conversely, decreased PP2A methylation and PP2A/Bα levels in AD will disrupt normal PP2A-tau interactions (Sontag et al., 2007), thereby preventing PP2A-mediated tau dephosphorylation while allowing for enhanced binding of Fyn kinase or other regulators to the tau proteins. PubMed:24653673

The deregulation of PP2A methylation in AD is especially interesting, not only because it can lead to a loss of PP2A/Bα, a major tau regulator, but also because PP2A methylation state is intimately linked to the integrity of one-carbon metabolism, which regulates SAM supply (Reviewed in Fowler,2005). PubMed:24653673