Centre for Systems Biology, Lunenfeld Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
Programme équipe Labellisée Ligue Contre le Cancer, Institut Jacques Monod, UMR7592, Université de Paris, CNRS, Paris, France.
Nat Commun. 2021 Mar 26;12(1):1899. doi: 10.1038/s41467-021-21922-w.
Polo-like kinase 1 (Plk1) is instrumental for mitotic entry and progression. Plk1 is activated by phosphorylation on a conserved residue Thr210 in its activation segment by the Aurora A kinase (AURKA), a reaction that critically requires the co-factor Bora phosphorylated by a CyclinA/B-Cdk1 kinase. Here we show that phospho-Bora is a direct activator of AURKA kinase activity. We localize the key determinants of phospho-Bora function to a 100 amino acid region encompassing two short Tpx2-like motifs and a phosphoSerine-Proline motif at Serine 112, through which Bora binds AURKA. The latter substitutes in trans for the Thr288 phospho-regulatory site of AURKA, which is essential for an active conformation of the kinase domain. We demonstrate the importance of these determinants for Bora function in mitotic entry both in Xenopus egg extracts and in human cells. Our findings unveil the activation mechanism of AURKA that is critical for mitotic entry.
丝氨酸/苏氨酸蛋白激酶 Polo 样激酶 1（Plk1）对于有丝分裂的进入和进程至关重要。Plk1 通过其激活结构域中的保守残基 Thr210 上的磷酸化被 Aurora A 激酶（AURKA）激活，该反应需要细胞周期蛋白 A/B-Cdk1 激酶磷酸化的辅助因子 Bora。在这里，我们表明磷酸化 Bora 是 AURKA 激酶活性的直接激活剂。我们通过将关键决定因素定位到包含两个短 Tpx2 样基序和丝氨酸 112 处的磷酸丝氨酸-脯氨酸基序的 100 个氨基酸区域，来确定 Bora 与 AURKA 结合的位置。后者在反式中替代 AURKA 的 Thr288 磷酸化调节位点，这对于激酶结构域的活性构象至关重要。我们证明了这些决定因素在 Xenopus 卵提取物和人类细胞中进入有丝分裂过程中对 Bora 功能的重要性。我们的发现揭示了对于有丝分裂进入至关重要的 AURKA 激活机制。
