Revisiting degron motifs in human AURKA required for its targeting by APC/CFZR1

Mitotic kinase Aurora A (AURKA) diverges from other kinases in its multiple active conformations that may explain its interphase roles and the limited efficacy of drugs targeting the kinase pocket. Regulation of AURKA activity by the cell is critically dependent on destruction mediated by the anaphase-promoting complex (APC/C-FZR1) during mitotic exit and G1 phase and requires an atypical N-terminal degron in AURKA called the A-box in addition to a reported canonical D-box degron in the C-terminus. Here, we find that the reported C-terminal D-box of AURKA does not act as a degron and instead mediates essential structural features of the protein. In living cells, the N-terminal intrinsically disordered region of AURKA containing the A-box is sufficient to confer FZR1-dependent mitotic degradation. Both in silico and in cellulo assays predict the QRVL short linear interacting motif of the A-box to be a phospho-regulated D-box. We propose that degradation of full-length AURKA also depends on an intact C-terminal domain because of critical conformational parameters permissive for both activity and mitotic degradation of AURKA.

Automated summary

This research investigates the degradation mechanism of the mitotic kinase AURKA. The study finds that the C-terminal D-box of AURKA does not act as a degron but instead mediates essential structural features of the protein. It also shows that the N-terminal intrinsically disordered region of AURKA containing the A-box is sufficient for FZR1-dependent mitotic degradation. Additionally, the study suggests that the QRVL short linear interacting motif in the A-box may be a phospho-regulated D-box.