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

• DOI: 10.1038/ncomms11491
• Publication Date: 2016-05-13T10:34:39Z
• Authors: Karsten Boldt; Jeroen van Reeuwijk; Qianhao Lu; Konstantinos Kout...; Thanh-Minh T. Nguyen; Yves Texier; Sylvia E. C. van ...; 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 Johanne...; 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; 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; ; 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; David Fitzpatrick; 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 Onoufr...; Felicity Payne; Vincent Plagnol; Lucy Raymond; David B. Savage; Peter Scambler; Miriam Schmidts; Nadia Schoenmakers; Robert Semple; Eva Serra; Jim Stalker; Margriet van Koge...; Parthiban Vijayar...; Klaudia Walter; Ros Whittall; Kathy Williamson
• Keywords: Ciliogenesis; Organelle; Ciliopathies; Intraflagellar Transport; Ciliopathy; Proteostasis; Proteome; Exocyst

Abstract Cellular organelles provide opportunities to relate biological mechanisms disease. Here we use affinity proteomics, genetics and cell biology interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions 52 complexes. Reverse tagging, repetition purifications statistical analyses, produce high-resolution network that reveals organelle-specific complexes not apparent in larger studies, links vesicle transport, the cytoskeleton, signalling ubiquitination proteostasis. We observe sub-complexes exocyst intraflagellar transport complexes, which validate biochemically, by probing structurally predicted, disruptive, variants from disease patients. The suggests other diseases could be including 3M syndrome. show genes are involved ciliogenesis, patient fibroblasts lack cilia. Overall, this targeting strategy shows considerable promise for Systems Medicine.