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

Author

Listed:
  • Karsten Boldt

    (Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen)

  • Jeroen van Reeuwijk

    (Radboud University Medical Center)

  • Qianhao Lu

    (Biochemie Zentrum Heidelberg (BZH), University of Heidelberg
    Cell Networks, Bioquant, Ruprecht-Karl University of Heidelberg)

  • Konstantinos Koutroumpas

    (Institute of Systems and Synthetic Biology, Genopole, CNRS, Université d’Evry)

  • Thanh-Minh T. Nguyen

    (Radboud University Medical Center)

  • Yves Texier

    (Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen
    Helmholtz Center Munich, Center for Integrated Protein Science)

  • Sylvia E. C. van Beersum

    (Radboud University Medical Center)

  • Nicola Horn

    (Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen)

  • Jason R. Willer

    (Center for Human Disease Modeling, Duke University)

  • Dorus A. Mans

    (Radboud University Medical Center)

  • Gerard Dougherty

    (University Children's Hospital Muenster)

  • Ideke J. C. Lamers

    (Radboud University Medical Center)

  • Karlien L. M. Coene

    (Radboud University Medical Center)

  • Heleen H. Arts

    (Radboud University Medical Center)

  • Matthew J. Betts

    (Biochemie Zentrum Heidelberg (BZH), University of Heidelberg
    Cell Networks, Bioquant, Ruprecht-Karl University of Heidelberg)

  • Tina Beyer

    (Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen)

  • Emine Bolat

    (Radboud University Medical Center)

  • Christian Johannes Gloeckner

    (German Center for Neurodegenerative Diseases (DZNE) within the Helmholz Association)

  • Khatera Haidari

    (Regenerative Medicine Center, University Medical Center Utrecht)

  • Lisette Hetterschijt

    (Cognition and Behaviour, Radboud University Medical Center)

  • Daniela Iaconis

    (Telethon Institute of Genetics and Medicine)

  • Dagan Jenkins

    (Molecular Medicine Unit and Birth Defects Research Centre, UCL Institute of Child Health)

  • Franziska Klose

    (Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen)

  • Barbara Knapp

    (Cell and Matrix Biology, Inst. of Zoology, Johannes Gutenberg University of Mainz)

  • Brooke Latour

    (Radboud University Medical Center)

  • Stef J. F. Letteboer

    (Radboud University Medical Center)

  • Carlo L. Marcelis

    (Radboud University Medical Center)

  • Dragana Mitic

    (Cambridge Cell Networks Ltd)

  • Manuela Morleo

    (Telethon Institute of Genetics and Medicine
    Department of Translational Medicine Federico II University)

  • Machteld M. Oud

    (Radboud University Medical Center)

  • Moniek Riemersma

    (Radboud University Medical Center)

  • Susan Rix

    (Molecular Medicine Unit and Birth Defects Research Centre, UCL Institute of Child Health)

  • Paulien A. Terhal

    (University Medical Center Utrecht)

  • Grischa Toedt

    (Structural and Computational Biology Unit, European Molecular Biology Laboratory)

  • Teunis J. P. van Dam

    (Centre for Molecular and Biomolecular Informatics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center)

  • Erik de Vrieze

    (Cognition and Behaviour, Radboud University Medical Center)

  • Yasmin Wissinger

    (Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen)

  • Ka Man Wu

    (Radboud University Medical Center)

  • Gordana Apic

    (Cambridge Cell Networks Ltd)

  • Philip L. Beales

    (Molecular Medicine Unit and Birth Defects Research Centre, UCL Institute of Child Health)

  • Oliver E. Blacque

    (School of Biomolecular & Biomed Science, Conway Institute, University College Dublin)

  • Toby J. Gibson

    (Structural and Computational Biology Unit, European Molecular Biology Laboratory)

  • Martijn A. Huynen

    (Centre for Molecular and Biomolecular Informatics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center)

  • Nicholas Katsanis

    (Center for Human Disease Modeling, Duke University)

  • Hannie Kremer

    (Cognition and Behaviour, Radboud University Medical Center)

  • Heymut Omran

    (University Children's Hospital Muenster)

  • Erwin van Wijk

    (Cognition and Behaviour, Radboud University Medical Center)

  • Uwe Wolfrum

    (Cell and Matrix Biology, Inst. of Zoology, Johannes Gutenberg University of Mainz)

  • François Kepes

    (Institute of Systems and Synthetic Biology, Genopole, CNRS, Université d’Evry)

  • Erica E. Davis

    (Center for Human Disease Modeling, Duke University)

  • Brunella Franco

    (Telethon Institute of Genetics and Medicine
    Department of Translational Medicine Federico II University)

  • Rachel H. Giles

    (Regenerative Medicine Center, University Medical Center Utrecht)

  • Marius Ueffing

    (Medical Proteome Center, Institute for Ophthalmic Research, University of Tuebingen)

  • Robert B. Russell

    (Biochemie Zentrum Heidelberg (BZH), University of Heidelberg
    Cell Networks, Bioquant, Ruprecht-Karl University of Heidelberg)

  • Ronald Roepman

    (Radboud University Medical Center)

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.

Suggested Citation

  • 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 Dou, 2016. "An organelle-specific protein landscape identifies novel diseases and molecular mechanisms," Nature Communications, Nature, vol. 7(1), pages 1-13, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11491
    DOI: 10.1038/ncomms11491
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    Cited by:

    1. Jens S. Andersen & Aaran Vijayakumaran & Christopher Godbehere & Esben Lorentzen & Vito Mennella & Kenneth Bødtker Schou, 2024. "Uncovering structural themes across cilia microtubule inner proteins with implications for human cilia function," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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