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Cryo-EM structure of the PP2A:B55-FAM122A complex, PP2Ac body
Structural highlights
Function2AAA_HUMAN The PR65 subunit of protein phosphatase 2A serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit. Required for proper chromosome segregation and for centromeric localization of SGOL1 in mitosis.[1] Publication Abstract from PubMedProgression through the cell cycle is controlled by regulated and abrupt changes in phosphorylation(1). Mitotic entry is initiated by increased phosphorylation of mitotic proteins, a process driven by kinases(2), whereas mitotic exit is achieved by counteracting dephosphorylation, a process driven by phosphatases, especially PP2A:B55(3). Although the role of kinases in mitotic entry is well established, recent data have shown that mitosis is only successfully initiated when the counterbalancing phosphatases are also inhibited(4). Inhibition of PP2A:B55 is achieved by the intrinsically disordered proteins ARPP19(5,6) and FAM122A(7). Despite their critical roles in mitosis, the mechanisms by which they achieve PP2A:B55 inhibition is unknown. Here, we report the single-particle cryo-electron microscopy structures of PP2A:B55 bound to phosphorylated ARPP19 and FAM122A. Consistent with our complementary NMR spectroscopy studies, both intrinsically disordered proteins bind PP2A:B55, but do so in highly distinct manners, leveraging multiple distinct binding sites on B55. Our extensive structural, biophysical and biochemical data explain how substrates and inhibitors are recruited to PP2A:B55 and provide a molecular roadmap for the development of therapeutic interventions for PP2A:B55-related diseases. Cryo-EM structures of PP2A:B55-FAM122A and PP2A:B55-ARPP19.,Padi SKR, Vos MR, Godek RJ, Fuller JR, Kruse T, Hein JB, Nilsson J, Kelker MS, Page R, Peti W Nature. 2024 Jan;625(7993):195-203. doi: 10.1038/s41586-023-06870-3. Epub 2023 , Dec 20. PMID:38123684[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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