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

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  • Karsten Boldt
  • Jeroen Van Reeuwijk
  • Qianhao Lu
  • Konstantinos Koutroumpas
  • Thanh Minh T. Nguyen
  • Yves Texier
  • Sylvia E.C. Van Beersum
  • Nicola Horn
  • Jason R. Willer
  • Dorus A. Mans
  • Gerard Dougherty
  • Ideke J.C. Lamers
  • Karlien L.M. Coene
  • Heleen H. Arts
  • Matthew J. Betts
  • Tina Beyer
  • Emine Bolat
  • Christian Johannes Gloeckner
  • Khatera Haidari
  • Lisette Hetterschijt
  • Daniela Iaconis
  • Dagan Jenkins
  • Franziska Klose
  • Barbara Knapp
  • Brooke Latour
  • Stef J.F. Letteboer
  • Carlo L. Marcelis
  • Dragana Mitic
  • Manuela Morleo
  • Machteld M. Oud
  • Moniek Riemersma
  • Susan Rix
  • Paulien A. Terhal
  • Grischa Toedt
  • Teunis J.P. Van Dam
  • Erik De Vrieze
  • Yasmin Wissinger
  • Ka Man Wu
  • Saeed Al-Turki
  • Carl Anderson
  • Dinu Antony
  • Inês Barroso
  • Jamie Bentham
  • Shoumo Bhattacharya
  • Keren Carss
  • Krishna Chatterjee
  • Sebahattin Cirak
  • Catherine Cosgrove
  • Petr Danecek
  • Richard Durbin
  • Jamie Floyd
  • A. Reghan Foley
  • Chris Franklin
  • Marta Futema
  • Steve E. Humphries
  • Matt Hurles
  • Chris Joyce
  • Shane McCarthy
  • Hannah M. Mitchison
  • Dawn Muddyman
  • Francesco Muntoni
  • Stephen O'Rahilly
  • Alexandros Onoufriadis
  • Felicity Payne
  • Vincent Plagnol
  • Lucy Raymond
  • David B. Savage
  • Peter Scambler
  • Miriam Schmidts
  • Nadia Schoenmakers
  • Robert Semple
  • Eva Serra
  • Jim Stalker
  • Margriet Van Kogelenberg
  • Parthiban Vijayarangakannan
  • Klaudia Walter
  • Ros Whittall
  • Gordana Apic
  • Philip L. Beales
  • Oliver E. Blacque
  • Toby J. Gibson
  • Martijn A. Huynen
  • Nicholas Katsanis
  • Hannie Kremer
  • Heymut Omran
  • Erwin Van Wijk
  • Uwe Wolfrum
  • François Kepes
  • Erica E. Davis
  • Brunella Franco
  • Rachel H. Giles
  • Marius Ueffing
  • Robert B. Russell
  • Ronald Roepman

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Original languageEnglish
Article number11491
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 13 May 2016

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.

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