9O04

CryoEM structure of the FBXO42-CCDC6-PP2Ac degradasome

Summary for 9O04

• Entry DOI: 10.2210/pdb9o04/pdb
• EMDB information: 49966
• Descriptor: Coiled-coil domain-containing protein 6, F-box only protein 42, Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform, ... (5 entities in total)
• Functional Keywords: e3 ligase, phosphatase, scaffolding, transferase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 14
• Total formula weight: 606641.22

Authors

Hsu, P.L.,Michaelian, N.,Azumaya, C.,Coassolo, S.,Yauch, R.L. (deposition date: 2025-04-02, release date: 2026-01-21, Last modification date: 2026-04-29)

Primary citation

Coassolo, S.,Michaelian, N.,Maculins, T.,Azumaya, C.M.,Cheung, T.K.,Yin, J.,Zilberleyb, I.,Pahuja, K.B.,Garner, T.,Lau, T.,Mau, D.,Grimmer, M.,Fortin, J.P.,Costa, M.,Dimitrova, Y.N.,Rose, C.M.,Hsu, P.L.,Yauch, R.L.
Template-driven scaffolding of SCF FBXO42 regulates PP2A degradation.
Nature, 2026

PubMed Abstract: Protein phosphatase 2A (PP2A) is a Ser/Thr phosphatase that regulates the phosphorylation of almost all cellular processes, including cell division and proliferation. PP2A forms heterotrimeric holoenzyme complexes comprising a catalytic subunit (PP2Ac), a scaffolding subunit (PP2Aa) and variable B regulatory subunits that exert precise control over enzyme substrate specificity and prevent indiscriminate dephosphorylation of phosphoproteins. However, the mechanisms that control the activity of uncomplexed catalytic subunits have remained relatively unclear. Here we find that the E3 ligase SKP1-CUL1-F-box (SCF) complex containing F-box other protein 42 (FBXO42, also known as JFK; hereafter, SCF) degrades holoenzyme-free PP2Ac in a complex with the coiled-coil protein CCDC6 to maintain cancer cell fitness. The cryo-electron microscopy structure of the FBXO42-CCDC6-PP2Ac assembly reveals a pseudosymmetric architecture in which CCDC6 forms a central dimeric template that recruits multiple copies of PP2Ac and creates a substrate for FBXO42. Both the quaternary structure of this CCDC6-PP2Ac heterodimer and the post-translationally methylated tail of PP2Ac are recognized by FBXO42 for ubiquitination. The multivalent structure facilitated by CCDC6 enables the assembly of multiple degradation complexes along a single coiled coil, leading to the turnover of free phosphatases and downregulation of catalytic activity. Together, our findings define a mechanism for PP2A control through the ubiquitin-proteosome system and establish a paradigm for cullin-RING ligase-substrate interactions.

PubMed: 41986709
DOI: 10.1038/s41586-026-10368-z

Experimental method

ELECTRON MICROSCOPY (3.2 Å)