An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.
An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.
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DOI：
10.1038/ncomms11491
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发表时间：
2016-05-13
影响因子：
16.6
通讯作者：
UK10K Rare Diseases Group
中科院分区：
文献类型：
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作者：
Boldt K;van Reeuwijk J;Lu Q;Koutroumpas K;Nguyen TM;Texier Y;van Beersum SE;Horn N;Willer JR;Mans DA;Dougherty G;Lamers IJ;Coene KL;Arts HH;Betts MJ;Beyer T;Bolat E;Gloeckner CJ;Haidari K;Hetterschijt L;Iaconis D;Jenkins D;Klose F;Knapp B;Latour B;Letteboer SJ;Marcelis CL;Mitic D;Morleo M;Oud MM;Riemersma M;Rix S;Terhal PA;Toedt G;van Dam TJ;de Vrieze E;Wissinger Y;Wu KM;Apic G;Beales PL;Blacque OE;Gibson TJ;Huynen MA;Katsanis N;Kremer H;Omran H;van Wijk E;Wolfrum U;Kepes F;Davis EE;Franco B;Giles RH;Ueffing M;Russell RB;Roepman R;UK10K Rare Diseases Group
细胞器提供了将生物学机制与疾病联系起来的机会。在这里，我们使用亲和蛋白质组学，遗传学和细胞生物学来询问纤毛：知之甚少的细胞器，缺陷会导致遗传疾病。217个标记的人类纤毛蛋白质创建了1，319个蛋白质，4，905个相互作用和52个复合物的最终景观。反向标记、重复纯化和统计分析产生了一个高分辨率网络，揭示了在大型研究中不明显的细胞器特异性相互作用和复合物，并将囊泡转运、细胞骨架、信号传导和遍在化与纤毛信号传导和蛋白质稳态联系起来。我们观察子复合物的囊外和鞭毛内运输复合物，我们验证生化，并通过探测结构预测，破坏性，遗传变异的睫状体疾病患者。景观表明其他遗传疾病可能是睫状体，包括3M综合征。我们发现，3M基因参与纤毛发生，患者成纤维细胞缺乏纤毛。总体而言，这种细胞器特异性靶向策略显示出系统医学的巨大潜力。 定位于初级纤毛的蛋白质突变会导致毁灭性的疾病，然而初级纤毛是一个知之甚少的细胞器。在这里，作者使用相互作用蛋白质组学来识别人类纤毛蛋白的网络，为几种生物过程和疾病提供了新的见解。
Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine. Mutations in proteins that localize to primary cilia cause devastating diseases, yet the primary cilium is a poorly understood organelle. Here the authors use interaction proteomics to identify a network of human ciliary proteins that provides new insights into several biological processes and diseases.