TY - JOUR T1 - Revisiting degron motifs in human AURKA required for its targeting by APC/C<sup>FZR1</sup> JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.202201372 VL - 6 IS - 2 SP - e202201372 AU - Ahmed Abdelbaki AU - Camilla Ascanelli AU - Cynthia N Okoye AU - H Begum Akman AU - Giacomo Janson AU - Mingwei Min AU - Chiara Marcozzi AU - Anja Hagting AU - Rhys Grant AU - Maria De Luca AU - Italia Anna Asteriti AU - Giulia Guarguaglini AU - Alessandro Paiardini AU - Catherine Lindon Y1 - 2023/02/01 UR - https://www.life-science-alliance.org/content/6/2/e202201372.abstract N2 - 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/CFZR1) 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. ER -