Structural basis of PP2A phosphatase activator reveals a unique chaperone function in PP2A activation

Abstract

Protein Phosphatase 2A (PP2A) is one of the most important phosphatases essential for many cellular processes. PP2A Phosphatase Activator (PTPA) plays an important role in PP2A activation. The underlying mechanism remained unclear. To determine the structural basis of PP2A activation, we determined the crystal structure of the PP2A‐PTPA‐ATPγS complex at 2.8 Å and PP2A‐PTPA‐ADP:AlF4− complex at 1.9 Å. The structures reveal that PTPA possesses an unexpected chaperone function that stabilizes an active conformation of the PP2A C subunit (PP2Ac) active site required for stable loading of catalytic metal ions. PTPA and PP2Ac form an unconventional ATPase machinery. Assisted by PTPA, ATP β/γ phosphates bind directly to the PP2A active site pocket, forming a typical double‐octahedral chelation of catalytic metal ions together with metal chelating residues. This atomic architecture underlies a composite ATPase activity of the PP2A‐PTPA complex that utilizes PP2A's phosphatase active site upon activation. In summary, our studies uncover that PTPA is a robust activation chaperone with a unique mechanism in PP2A activation, and provide novel insights into chaperone‐mediated activation of signaling proteins. This work was supported by University of Wisconsin‐Madison (Y. Xing), ACS research scholar grant (Y. Xing), and R01 GM096060–01 (Y. Xing).