| Abstract |
Protein phosphatase PP2A-the most abundant Ser/Thr phosphatase in cells-is a heterotrimeric holoenzyme comprising a catalytic subunit, a scaffold subunit, and a regulatory subunit. The B55 regulatory subunit is primarily localized in the cytoplasm, where it provides a surface for recruiting substrates and regulatory proteins to the PP2A:B55 holoenzyme. SERTAD family proteins-SERTAD1, SERTAD2, SERTAD3, SERTAD4, and CDCA4-share a SERTA domain that binds to the B55 subunit. In this study, we aimed to demonstrate that SERTAD proteins function as substrate adapters and induce dephosphorylation at Ser178 of CDC25A, which is crucial for activating cyclin-dependent kinases. The conserved properties of SERTAD proteins-namely, nuclear localization and B55-binding-are necessary for the dephosphorylation of nuclear CDC25A and the subsequent dissociation of the inhibitory protein 14-3-3. Structural modeling and mutational analysis further revealed that the SERTA/B55-binding domain interacts directly with CDC25A, positioning its Ser178 close to the active site of PP2A:B55. Collectively, these results suggested that the SERTA/B55-binding domain provides a new surface for substrate binding.
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