Download MendeleyStructural mechanism for recognition of E2F1 by the ubiquitin ligase adaptor Cyclin F.
Ngoi, P., Wang, X., Putta, S., Da Luz, R.F., Serrao, V.H.B., Emanuele, M.J., Rubin, S.M.(2025) bioRxiv
- PubMed: 39868286
- DOI: https://doi.org/10.1101/2025.01.15.633208
- Primary Citation of Related Structures:
9CB3 - PubMed Abstract:
Cyclin F, a non-canonical member of the cyclin protein family, plays a critical role in regulating the precise transitions of cell-cycle events. Unlike canonical cyclins, which bind and activate cyclin-dependent kinases (CDKs), Cyclin F functions as a substrate receptor protein within the Skp1-Cullin-F box (SCF) E3 ubiquitin ligase complex, enabling the ubiquitylation of target proteins. The structural features that distinguish Cyclin F as a ligase adaptor and the mechanisms underlying its selective substrate recruitment over Cyclin A, which functions in complex with CDK2 at a similar time in the cell cycle, remain largely unexplored. We utilized single-particle cryo-electron microscopy to elucidate the structure of a Cyclin F-Skp1 complex bound to an E2F1 peptide. The structure and biochemical analysis reveal important differences in the substrate-binding site of Cyclin F compared to Cyclin A. Our findings expand on the canonical cyclin-binding motif (Cy or RxL) and highlight the importance of electrostatics at the E2F1 binding interface, which varies for Cyclin F and Cyclin A. Our results advance our understanding of E2F1 regulation and may inform the development of inhibitors targeting Cyclin F.
Organizational Affiliation:
Department of Chemistry and Biochemistry, University of California, Santa Cruz, CA.
