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An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.


ABSTRACT: 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.

SUBMITTER: Boldt K 

PROVIDER: S-EPMC4869170 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.

Boldt Karsten K   van Reeuwijk Jeroen J   Lu Qianhao Q   Koutroumpas Konstantinos K   Nguyen Thanh-Minh T TM   Texier Yves Y   van Beersum Sylvia E C SE   Horn Nicola N   Willer Jason R JR   Mans Dorus A DA   Dougherty Gerard G   Lamers Ideke J C IJ   Coene Karlien L M KL   Arts Heleen H HH   Betts Matthew J MJ   Beyer Tina T   Bolat Emine E   Gloeckner Christian Johannes CJ   Haidari Khatera K   Hetterschijt Lisette L   Iaconis Daniela D   Jenkins Dagan D   Klose Franziska F   Knapp Barbara B   Latour Brooke B   Letteboer Stef J F SJ   Marcelis Carlo L CL   Mitic Dragana D   Morleo Manuela M   Oud Machteld M MM   Riemersma Moniek M   Rix Susan S   Terhal Paulien A PA   Toedt Grischa G   van Dam Teunis J P TJ   de Vrieze Erik E   Wissinger Yasmin Y   Wu Ka Man KM   Apic Gordana G   Beales Philip L PL   Blacque Oliver E OE   Gibson Toby J TJ   Huynen Martijn A MA   Katsanis Nicholas N   Kremer Hannie H   Omran Heymut H   van Wijk Erwin E   Wolfrum Uwe U   Kepes François F   Davis Erica E EE   Franco Brunella B   Giles Rachel H RH   Ueffing Marius M   Russell Robert B RB   Russell Robert B RB   Roepman Ronald R  

Nature communications 20160513


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-  ...[more]

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