Cyclin E1 contains a Cul3 degron that is absent in cyclin E2. (A) The proposed helix (A, represented by the red bar) overlaps the DPDEE (Cul3 binding) and KIDR (ubiquitylation site) alanine-scanning mutants (shown in red). (B) The Cul3 degron is highly conserved in mouse (Mus musculus) and rat (Rattus norvegicus) cyclin E1 (outlined in red). (C) Sequence comparison of the degron region in cyclin E1 (bottom) to the same region in cyclin E2 (top). Chou–Fasman analysis of the amino acid sequences suggests that the structures differ between cyclin E1 and cyclin E2. Additionally, the Cul3 degron in cyclin E1 is acidic, with a net charge of minus two (difference between the number of acidic residues and the number of basic residues). The same region in cyclin E2 is basic with a net charge of plus four. (D) Western blots (WB) level of transfected Myc-tagged cyclin E2, shown here in duplicate in WT (lanes 1 and 3) and Cul3 KO (lanes 2 and 4) HEK 293 cells. (E) Myc-tagged WT cyclin E1 (lanes 1 and 2), the 48–51 (KIDR) alanine-scanning mutant (lanes 3 and 4), and Myc–cyclin E2 (lanes 5 and 6) were transfected into HEK293 cells in the presence and absence of Flag–Cul3 and immunoprecipitated (IP) using an anti-Flag antibody. Upper blot: Flag IP, Myc western blot showing the IP results. Lower blots: western blots showing protein expression levels. For all western blots, the migration of size markers is indicated on the sides of the gel images (kDa).