The conserved Spd-2/CEP192 domain adopts a unique protein fold to promote centrosome scaffold assembly

IF 12.5 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-03-19 DOI:10.1126/sciadv.adr5744

Liuyi Hu, Alan Wainman, Antonina Andreeva, Muladili Apizi, Ines Alvarez-Rodrigo, Siu-Shing Wong, Saroj Saurya, Devon Sheppard, Matthew Cottee, Steven Johnson, Susan M. Lea, Jordan W. Raff, Mark van Breugel, Zhe Feng

{"title":"The conserved Spd-2/CEP192 domain adopts a unique protein fold to promote centrosome scaffold assembly","authors":"Liuyi Hu, Alan Wainman, Antonina Andreeva, Muladili Apizi, Ines Alvarez-Rodrigo, Siu-Shing Wong, Saroj Saurya, Devon Sheppard, Matthew Cottee, Steven Johnson, Susan M. Lea, Jordan W. Raff, Mark van Breugel, Zhe Feng","doi":"10.1126/sciadv.adr5744","DOIUrl":null,"url":null,"abstract":"<div >Centrosomes form when centrioles assemble pericentriolar material (PCM) around themselves. Spd-2/CEP192 proteins, defined by a conserved “Spd-2 domain” (SP2D) comprising two closely spaced AspM-Spd-2-Hydin (ASH) domains, play a critical role in centrosome assembly. Here, we show that the SP2D does not target <i>Drosophila</i> Spd-2 to centrosomes but rather promotes PCM scaffold assembly. Crystal structures of the human and honeybee SP2D reveal an unusual “extended cradle” structure mediated by a conserved interaction interface between the two ASH domains. Mutations predicted to perturb this interface, including a human mutation associated with male infertility and Mosaic Variegated Aneuploidy, disrupt PCM scaffold assembly in flies. The SP2D is monomeric in solution, but the <i>Drosophila</i> SP2D can form higher-order oligomers upon phosphorylation by PLK1 (Polo-like kinase 1). Crystal-packing interactions and AlphaFold predictions suggest how SP2Ds might self-assemble, and mutations associated with one such potential dimerization interface markedly perturb SP2D oligomerization in vitro and PCM scaffold assembly in vivo.</div>","PeriodicalId":21609,"journal":{"name":"Science Advances","volume":"11 12","pages":""},"PeriodicalIF":12.5000,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciadv.adr5744","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Advances","FirstCategoryId":"103","ListUrlMain":"https://www.science.org/doi/10.1126/sciadv.adr5744","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}

引用次数: 0

Abstract

Centrosomes form when centrioles assemble pericentriolar material (PCM) around themselves. Spd-2/CEP192 proteins, defined by a conserved “Spd-2 domain” (SP2D) comprising two closely spaced AspM-Spd-2-Hydin (ASH) domains, play a critical role in centrosome assembly. Here, we show that the SP2D does not target Drosophila Spd-2 to centrosomes but rather promotes PCM scaffold assembly. Crystal structures of the human and honeybee SP2D reveal an unusual “extended cradle” structure mediated by a conserved interaction interface between the two ASH domains. Mutations predicted to perturb this interface, including a human mutation associated with male infertility and Mosaic Variegated Aneuploidy, disrupt PCM scaffold assembly in flies. The SP2D is monomeric in solution, but the Drosophila SP2D can form higher-order oligomers upon phosphorylation by PLK1 (Polo-like kinase 1). Crystal-packing interactions and AlphaFold predictions suggest how SP2Ds might self-assemble, and mutations associated with one such potential dimerization interface markedly perturb SP2D oligomerization in vitro and PCM scaffold assembly in vivo.

Abstract Image

查看原文本刊更多论文

保守的Spd-2/CEP192结构域采用独特的蛋白折叠促进中心体支架组装

中心体是中心粒在自身周围聚集中心周物质（PCM）形成的。Spd-2/CEP192蛋白由保守的“Spd-2结构域”（SP2D）定义，包括两个紧密间隔的AspM-Spd-2-Hydin （ASH）结构域，在中心体组装中起关键作用。在这里，我们发现SP2D并不将果蝇Spd-2靶向中心体，而是促进PCM支架组装。人类和蜜蜂SP2D的晶体结构揭示了由两个ASH域之间的保守相互作用界面介导的不寻常的“扩展摇篮”结构。据预测，干扰这一界面的突变，包括与雄性不育和马赛克杂色非整倍体相关的人类突变，会破坏果蝇的PCM支架组装。SP2D在溶液中是单体的，但果蝇SP2D可以在PLK1 （polo样激酶1）磷酸化后形成高阶低聚物。晶体包装相互作用和AlphaFold预测表明SP2D可能如何自组装，并且与这种潜在二聚化界面相关的突变显着干扰SP2D在体外的寡聚化和PCM支架在体内的组装。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.