Revisiting degron motifs in human AURKA required for its targeting by APC/C-FZR1
Revisiting degron motifs in human AURKA required for its targeting by APC/C-FZR1
复制标题
重新审视 AURKA 中 APC/C-FZR1 靶向所需的降解决定子基序
DOI：
10.1101/2022.01.31.478464
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Abdelbaki A
中科院分区：
文献类型：
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作者：
Abdelbaki A
有丝分裂激酶Aurora A （AURKA）与其他激酶的多种活性构象不同，这可能解释了它的间期作用和靶向激酶口袋的药物的有限疗效。细胞对AURKA活性的调节严重依赖于有丝分裂退出期和G1期后期促进复合体（APC/CFZR1）介导的破坏，并且需要AURKA中的非典型n端degron称为“a -box”，此外还需要c端典型D-box degron。在这里，我们发现报道的AURKA的c端D-box不作为degron，而是介导蛋白质的基本结构特征。在活细胞中，含有A-box的AURKA的n端固有紊乱区域足以导致fzr1依赖性的有丝分裂降解。在硅和纤维素分析中预测a -box的QRVL短线性相互作用基序是磷酸化调节的D-box。我们认为全长AURKA的降解也取决于完整的c端结构域，因为AURKA的活性和有丝分裂降解的关键构象参数是允许的。
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.