Protein Phosphatase 5-Recruiting Chimeras for Accelerating Tau Dephosphorylation

Hyperphosphorylation of proteins is implicated in various diseases, such as phosphorylated Tau (p-Tau), which is the main cause of Alzheimer's disease (AD). Dephosphorylation strategies have still been limited. Currently, phosphatase recruitment chimeras (PHORCs) have become a potential strategy for accelerating the dephosphorylation of proteins. However, PHORCs are still in the proof-of-concept stage. The paucity of available phosphatase effectors and the lack of effective methods to identify the appropriate length of the linker impede the development of PHORCs. Protein phosphatase 5 (PP5) is responsible for dephosphorylation of p-Tau in the brain. PP5 is distinct from other phosphatases, with a unique activation mechanism. We demonstrated that PP5 can be simultaneously recruited and activated for the design of PHORCs, exhibiting a synergistic advantage for accelerating dephosphorylation of p-Tau. Moreover, we attempted computation-aided prediction methods to obtain the potential length of the linker, promoting the rational design of PHORCs. Therefore, our study provides critical insights into the development of PHORCs and proposes new ideas for accelerating the design of heterotrimeric chimeras.