6nts | pdb_00006nts
Protein Phosphatase 2A (Aalpha-B56alpha-Calpha) holoenzyme in complex with a Small Molecule Activator of PP2A (SMAP)
Structural highlights
Function[2AAA_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] [PP2AA_HUMAN] PP2A is the major phosphatase for microtubule-associated proteins (MAPs). PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase. Cooperates with SGOL2 to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I (By similarity). Can dephosphorylate SV40 large T antigen and p53/TP53. Activates RAF1 by dephosphorylating it at 'Ser-259'.[2] [3] [4] [2A5A_HUMAN] The B regulatory subunit might modulate substrate selectivity and catalytic activity, and also might direct the localization of the catalytic enzyme to a particular subcellular compartment. Publication Abstract from PubMedImpairment of protein phosphatases, including the family of serine/threonine phosphatases designated PP2A, is essential for the pathogenesis of many diseases, including cancer. The ability of PP2A to dephosphorylate hundreds of proteins is regulated by over 40 specificity-determining regulatory "B" subunits that compete for assembly and activation of heterogeneous PP2A heterotrimers. Here, we reveal how a small molecule, DT-061, specifically stabilizes the B56alpha-PP2A holoenzyme in a fully assembled, active state to dephosphorylate selective substrates, such as its well-known oncogenic target, c-Myc. Our 3.6 A structure identifies molecular interactions between DT-061 and all three PP2A subunits that prevent dissociation of the active enzyme and highlight inherent mechanisms of PP2A complex assembly. Thus, our findings provide fundamental insights into PP2A complex assembly and regulation, identify a unique interfacial stabilizing mode of action for therapeutic targeting, and aid in the development of phosphatase-based therapeutics tailored against disease specific phospho-protein targets. Selective PP2A Enhancement through Biased Heterotrimer Stabilization.,Leonard D, Huang W, Izadmehr S, O'Connor CM, Wiredja DD, Wang Z, Zaware N, Chen Y, Schlatzer DM, Kiselar J, Vasireddi N, Schuchner S, Perl AL, Galsky MD, Xu W, Brautigan DL, Ogris E, Taylor DJ, Narla G Cell. 2020 Apr 30;181(3):688-701.e16. doi: 10.1016/j.cell.2020.03.038. Epub 2020 , Apr 20. PMID:32315618[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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