Template-driven scaffolding of SCFFBXO42 regulates PP2A degradation
) 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.
Authors
- Yoana N. Dimitrova (ORCID: https://orcid.org/0000-0003-1547-5781)
- Peter Hsu (ORCID: https://orcid.org/0000-0002-9381-6564)
- Inna Zilberleyb
- Tommy K. Cheung
- Kanika Bajaj Pahuja (ORCID: https://orcid.org/0000-0001-8977-9812)
- Timurs Maculins (ORCID: https://orcid.org/0000-0002-9333-301X)
- Robert L. Yauch (ORCID: https://orcid.org/0000-0001-9478-6283)
- Caleigh M. Azumaya (ORCID: https://orcid.org/0000-0002-3484-9921)
- Christopher M. Rose (ORCID: https://orcid.org/0000-0002-7502-3368)
- Sébastien Coassolo (ORCID: https://orcid.org/0000-0003-3669-8650)
- Mike Costa
- Matthew Grimmer (ORCID: https://orcid.org/0000-0001-5184-9168)
- Nairie Michaelian (ORCID: https://orcid.org/0000-0003-1605-1788)
- Jianping Yin (ORCID: https://orcid.org/0000-0003-0425-5804)
- Thomas P. Garner
- Davis Mau (ORCID: https://orcid.org/0009-0002-3441-1249)
- Ted Lau
- Jean-Philippe Fortin
Institutions
- University of Wisconsin–Madison (US)
- Gene Therapy Laboratory (FR)
- Genomic Health (United States) (US)
- Sunesis (United States) (US)
Publication Details
- Journal
- Nature
- Published
- 2026-04-15
- DOI
- https://doi.org/10.1038/s41586-026-10368-z
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00