Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication.
Centriolar satellites assemble centrosomal microcephaly proteins to recruit CDK2 and promote centriole duplication.
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DOI：
10.7554/elife.07519
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发表时间：
2015-08-22
期刊：
影响因子：
7.7
通讯作者：
Reiter JF
中科院分区：
文献类型：
--
作者：
Kodani A;Yu TW;Johnson JR;Jayaraman D;Johnson TL;Al-Gazali L;Sztriha L;Partlow JN;Kim H;Krup AL;Dammermann A;Krogan NJ;Walsh CA;Reiter JF
原发性小头畸形 (MCPH) 相关蛋白 CDK5RAP2、CEP152、WDR62 和 CEP63 共定位于中心体。我们发现它们相互作用以促进中心粒复制并形成一个层次结构，其中每个都需要将另一个定位到中心体，CDK5RAP2位于顶点，CEP152、WDR62和CEP63依次位于较低位置。 MCPH 蛋白与不同的中心粒卫星蛋白相互作用； CDK5RAP2 与 SPAG5 和 CEP72 相互作用，CEP152 与 CEP131 相互作用，WDR62 与 MOONRAKER 相互作用，CEP63 与 CEP90 和 CCDC14 相互作用。这些卫星蛋白将其同源 MCPH 相互作用子定位于中心体，并促进中心粒复制。与卫星在小头畸形中的作用一致，卫星基因 CEP90 的纯合突变可能导致 MCPH。除 CCDC14 外，卫星蛋白和 MCPH 蛋白通过将 CDK2 招募到中心体来促进中心粒复制。因此，中心粒卫星构建了对人类神经发育至关重要的 MCPH 复合体，可促进 CDK2 中心体定位和中心粒复制。 DOI：http://dx.doi.org/10.7554/eLife.07519.001 当细胞分裂时，包含细胞遗传蓝图的染色体必须在两个新细胞之间复制和共享。称为中心体的结构组织细胞机器，在细胞分裂过程中分离染色体副本。每个中心体的中心有两个基于圆柱形微管的结构，称为中心粒。与中心体相互作用的某些蛋白质的突变会导致称为原发性小头畸形的神经发育障碍。出生时患有小头畸形的人的头部和大脑异常小。因此，他们可能在脑力任务上遇到困难。科学家们并不确切地知道这些“小头畸形相关”蛋白质通常如何与中心体相互作用或它们在中心体中的作用，因此很难弄清楚小头畸形患者出了什么问题。一种想法是，这些蛋白质有助于在细胞分裂之前复制中心粒。如果不发生这种复制，细胞就无法正常分裂；因此，患有干扰中心粒复制的突变的人无法生长出足够的脑细胞。现在，科达尼等人。研究了这些与小头畸形相关的蛋白质如何与聚集在中心体附近以复制中心粒的“卫星”蛋白质一起工作。卫星蛋白有助于将四种小头畸形相关蛋白招募到中心体，并在那里构建成一个环。小头畸形相关蛋白质以特定顺序聚集在中心体，每种蛋白质都会招募序列中的下一个蛋白质。一旦所有四个都位于中心体附近，一种有助于复制中心粒的酶就会将它们加入。进一步的实验表明，影响卫星蛋白之一（称为 CEP90）的突变可能会导致小头畸形。未来对小头畸形相关基因如何工作的分析可能会揭示中心粒参与大脑发育的细胞生物学机制。 DOI：http://dx.doi.org/10.7554/eLife.07519.002
Primary microcephaly (MCPH) associated proteins CDK5RAP2, CEP152, WDR62 and CEP63 colocalize at the centrosome. We found that they interact to promote centriole duplication and form a hierarchy in which each is required to localize another to the centrosome, with CDK5RAP2 at the apex, and CEP152, WDR62 and CEP63 at sequentially lower positions. MCPH proteins interact with distinct centriolar satellite proteins; CDK5RAP2 interacts with SPAG5 and CEP72, CEP152 with CEP131, WDR62 with MOONRAKER, and CEP63 with CEP90 and CCDC14. These satellite proteins localize their cognate MCPH interactors to centrosomes and also promote centriole duplication. Consistent with a role for satellites in microcephaly, homozygous mutations in one satellite gene, CEP90, may cause MCPH. The satellite proteins, with the exception of CCDC14, and MCPH proteins promote centriole duplication by recruiting CDK2 to the centrosome. Thus, centriolar satellites build a MCPH complex critical for human neurodevelopment that promotes CDK2 centrosomal localization and centriole duplication. DOI: http://dx.doi.org/10.7554/eLife.07519.001 When a cell divides, the chromosomes that contain the genetic blueprint for the cell must be replicated and shared between the two new cells. A structure called the centrosome organizes the cellular machinery that separates the chromosome copies during cell division. At the center of each centrosome are two cylindrical microtubule-based structures called centrioles. Mutations in certain proteins that interact with the centrosome cause a neurodevelopmental disorder called primary microcephaly. People born with microcephaly have unusually small heads and brains. As a result, they may have difficulties with mental tasks. Scientists do not know exactly how these ‘microcephaly-associated’ proteins normally interact with the centrosomes or what they do at the centrosomes, so it is difficult to work out what goes wrong in people with microcephaly. One idea is that the proteins help to duplicate the centrioles before a cell divides. If this duplication does not occur, a cell cannot divide properly; so, people with mutations that interfere with centriole duplication cannot grow enough brain cells. Now, Kodani et al. have examined how these microcephaly-associated proteins work with ‘satellite’ proteins that congregate near the centrosome to duplicate centrioles. The satellite proteins help to recruit four microcephaly-associated proteins to the centrosome, where they are built into a ring. The microcephaly-associated proteins congregate at the centrosome in a particular order, with each protein recruiting the next one in the sequence. Once all four are in place near the centrosome, an enzyme that helps to duplicate the centrioles joins them. Further experiments suggest that mutations that affect one of the satellite proteins—known as CEP90—may cause microcephaly. Future analysis of how microcephaly-associated genes work may reveal the cell biological mechanisms by which centrioles participate in brain development. DOI: http://dx.doi.org/10.7554/eLife.07519.002