Dzhindzhev Nikola S, Tzolovsky George, Lipinszki Zoltan, Schneider Sandra, Lattao Ramona, Fu Jingyan, Debski Janusz, Dadlez Michal, Glover David M
Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK.
Curr Biol. 2014 Nov 3;24(21):2526-32. doi: 10.1016/j.cub.2014.08.061. Epub 2014 Sep 25.
Centrioles are 9-fold symmetrical structures at the core of centrosomes and base of cilia whose dysfunction has been linked to a wide range of inherited diseases and cancer. Their duplication is regulated by a protein kinase of conserved structure, the C. elegans ZYG-1 or its Polo-like kinase 4 (Plk4) counterpart in other organisms. Although Plk4's centriolar partners and mechanisms that regulate its stability are known, its crucial substrates for centriole duplication have never been identified. Here we show that Drosophila Plk4 phosphorylates four conserved serines in the STAN motif of the core centriole protein Ana2 to enable it to bind and recruit its Sas6 partner. Ana2 and Sas6 normally load onto both mother and daughter centrioles immediately after their disengagement toward the end of mitosis to seed procentriole formation. Nonphosphorylatable Ana2 still localizes to the centriole but can no longer recruit Sas6 and centriole duplication fails. Thus, following centriole disengagement, recruitment of Ana2 and its phosphorylation by Plk4 are the earliest known events in centriole duplication to recruit Sas6 and thereby establish the architecture of the new procentriole engaged with its parent.
中心粒是位于中心体核心和纤毛基部的九重对称结构,其功能障碍与多种遗传性疾病和癌症有关。它们的复制由一种结构保守的蛋白激酶调控,即秀丽隐杆线虫中的ZYG-1或其他生物中其对应的类Polo样激酶4(Plk4)。尽管已知Plk4的中心粒伴侣及其调控稳定性的机制,但其在中心粒复制中的关键底物从未被鉴定出来。在这里,我们表明果蝇Plk4磷酸化中心粒核心蛋白Ana2的STAN基序中的四个保守丝氨酸,使其能够结合并招募其Sas6伴侣。Ana2和Sas6通常在有丝分裂末期二者分离后立即加载到母中心粒和子中心粒上,以启动原中心粒的形成。不可磷酸化的Ana2仍定位于中心粒,但不再能招募Sas6,中心粒复制失败。因此,在中心粒分离后,Ana2的招募及其被Plk4磷酸化是中心粒复制中最早已知的招募Sas6的事件,从而建立与其亲本相连的新原中心粒的结构。